Combination regimens using progesterone receptor modulators

ABSTRACT

This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure:                    
     wherein R 1  and R 2  may be single substituents or fused; R 3  is H, OH, NH 2 , C 1  to C 6  alkyl, COR C , or optionally substituted C 1  to C 6  alkyl, C 3  to C 6  alkenyl, or alkynyl; R C  is H, or optionally substituted C 1  to C 3  alkyl, aryl, C 1  to C 3  alkoxy, or C 1  to C 3  aminoalkyl; R 4  is H, halogen, CN, NO 2 , or optionally substituted C 1  to C 6  alkyl, alkynyl, C 1  to C 6  alkoxy, amino, or C 1  to C 6  aminoalkyl; and R 5  is a benzene ring, a five or six membered heterocyclic ring; or pharmaceutically acceptable salt thereof. Methods of treatment include contraception, secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, carcinomas, adenocarcinomas minimization of side effects, or food intake stimulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.09/552,350, filed Apr. 19, 2000, now U.S. Pat. No. 6,444,668, whichclaims the benefit of the priority of U.S. Provisional PatentApplication No. 60/229,346, filed May 4, 1999, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to regimens of administering compounds, which areantagonists of the progesterone receptor in combination with aprogestin, an estrogen, or both. Intracellular receptors (IR) form aclass of structurally related gene regulators known as “ligand dependenttranscription factors” (R. M. Evans, Science, 240, 889, 1988). Thesteroid receptor family is a subset of the IR family, includingprogesterone receptor (PR), estrogen receptor (ER), androgen receptor(AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).

The natural hormone, or ligand, for the PR is the steroid progesterone,but synthetic compounds, such as medroxyprogesterone acetate orlevonorgestrel, have been made which also serve as ligands. Once aligand is present in the fluid surrounding a cell, it passes through themembrane via passive diffusion, and binds to the IR to create areceptor/ligand complex. This complex binds to specific gene promoterspresent in the cell's DNA. Once bound to the DNA the complex modulatesthe production of mRNA and protein encoded by that gene.

A compound that binds to an IR and mimics the action of the naturalhormone is termed an agonist, whilst a compound which inhibits theeffect of the hormone is an antagonist.

PR antagonists may be used in contraception. In this context they may beadministered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261, 248,1995), in combination with a PR agonist (Kekkonen, et al, Fertility andSterility, 60, 610, 1993) or in combination with a partial ER antagonistsuch as tamoxifen (WO 96/19997 A1 Jul. 4, 1996). PR antagonists may alsobe useful for the treatment of hormone dependent breast cancers(Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed.Vedeckis) as well as uterine and ovarian cancers. PR antagonists mayalso be useful for the treatment of non-malignant chronic conditionssuch as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993)and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402,1991). PR antagonists may also be useful in hormone replacement therapyfor post menopausal patients in combination with a partial ER antagonistsuch as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists, such asmifepristone and onapristone, have been shown to be effective in a modelof hormone dependent prostate cancer, which may indicate their utilityin the treatment of this condition in men (Michna, et al, Ann. N.Y.Acad. Sci., 761, 224, 1995).

Jones, et al, (U.S. Pat. No. 5,688,810) describe PR antagonistdihydroquinoline 1.

Jones, et al, described the enol ether 2 (U.S. Pat. No. 5,693,646) as aPR ligand.

Jones, et al, described compound 3 (U.S. Pat. No. 5,696,127) as a PRligand.

Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J. Med.Chem., 41, 291, 1998).

Zhi, et al, described the ether 7 as a PR antagonist (J. Med. Chem., 41,291, 1998).

Combs, et al., disclosed the amide 8 as a ligand for the PR (J. Med.Chem., 38, 4880, 1995).

Perlman, et. al., described the vitamin D analog 9 as a PR ligand (Tet.Letters, 35, 2295, 1994).

Hamann, et al, described the PR antagonist 10 (Ann. N.Y. Acad. Sci.,761, 383, 1995).

Chen, et al, described the PR antagonist 11 (Chen, et al, POI-37,16^(th) Int. Cong. Het. Chem, Montana, 1997).

Kurihari, et. al., described the PR ligand 12 (J. Antibiotics, 50, 360,1997).

Narr et al. (German Patent, DE 3633861, CA 109:22973) claimed thatimidazobenzoxazinones, e.g. A, as cardotonics; Benzoxazin-2-ones, suchas brofoxine (B), being active as an anxiolytic was reported by Hartmannet al. (Proc. West. Pharmacol. Soc. 21, 51-55 (1978)); More recently, anumber of patents (e.g. Young et al. WO95/20389; Christ et al.WO98/14436) claimed quinazolin-2-ones and benzoxazin-2-ones such ascompound C1 and C2 as inhibitors of HIV reverse transcriptase.

U.S. Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimenscomprising an antiprogestin and a progestin wherein the progestin isadministered in the alternating presence and absence of anantiprogestin. The disclosed regimens also provide for use of anestrogen for a period of from 2-4 days to prevent breakthrough bleeding.

DESCRIPTION OF THE INVENTION

This invention provides combination therapies and dosing regimensutilizing antiprogestational agents in combination with one or moreprogestational agents. This invention further provides methods oftreatment and dosing regimens further utilizing in combination withthese antiprogestins and progestins, an estrogen, such as ethinylestradiol.

These regimens and combinations may be administered to a mammal toinduce contraception or for the treatment and/or prevention of secondaryamenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis;polycystic ovary syndrome, carcinomas and adenocarcinomas of theendometrium, ovary, breast, colon, prostate. Additional uses of theinvention include stimulation of food intake. The uses herein for thetreatment and/or prevention of the conditions or diseases describedabove includes the continuous administration or periodic discontinuationof administration of the invention to allow for minimization of effectdose or minimization of side effects or cyclic menstrual bleeding.

The use of this invention for contraception includes administration,preferably orally, to a female of child bearing age an antiprogestin incombination with an estrogen or progestin or both. These administrationregimens are preferably carried out over 28 consecutive days, with aterminal portion of the cycle containing administration of noprogestins, estrogens or anti-progestins.

The progestins of these combinations may be administered alone or incombination with an estrogen for the first 14-24 days of the cycle, theprogestins being administered at a dosage range equal in progestationalactivity to about 35 μg to about 150 μg levonorgestrel per day,preferably equal in activity to from about 35 μg to about 100 μglevonorgestrel per day. An antiprogestin may then be administered aloneor in combination with an estrogen for a period of 1 to 11 days to beginon any cycle day between day 14 and 24. The anti-progestin in thesecombinations may be administered at a dose of from about 2 μg to about50 μg per day and the estrogen may be administered at a dose of fromabout 10 μg to about 35 μg per day. In an oral administration, a packageor kit containing 28 tablets will include a placebo tablet on those dayswhen the antiprogestin or progestin or estrogen is not administered.

In a preferred embodiment of this invention, the progestins of thisinvention may be administered alone or in combination with estrogen forthe initial 18 to 21 days of a 28-day cycle, followed by administrationof an antiprogestin, alone or in combination with an estrogen, for from1 to 7 days.

The estrogen to be used in the combinations and formulations of thisinvention is preferably ethinyl estradiol.

Progestational agents useful with this invention include, but are notlimited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel,norethindrone, gestodene, norethindrone acetate, norgestimate,osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone,nomegestrol, or (17-deacetyl)norgestimate. Among the preferredprogestins for use in the combinations of this invention arelevonorgestrel, gestodene and trimegestone.

Examples of orally administered regimens of this invention over a 28 daycycle include administration of a progestational agent solely for thefirst 21 days at a daily dose equal in progestational activity to fromabout 35 to about 100 μg of levonorgestrel. An antiprogestin compound ofthis invention may then be administered at a daily dose of from about 2to 50 mg from day 22 to day 24, followed by no administration oradministration of a placebo for days 25 to 28. It is most preferred thatthe daily dosages of each relevant active ingredient be incorporatedinto a combined, single daily dosage unit, totaling 28 daily units per28-day cycle.

In another regimen, a progestational agent may be coadministered for thefirst 21 days at a daily dose equal in progestational activity to fromabout 35 to about 150 μg levonorgestrel, preferably equal in activity tofrom about 35 to about 100 μg levonorgestrel, with an estrogen, such asethinyl estradiol, at a daily dose range of from about 10 to about 35μg. This may be followed as described above with an antiprogestinadministered at a daily dose of from about 2 to 50 mg from day 22 to day24, followed by no administration or administration of a placebo fordays 25 to 28.

Still another regimen within the scope of this invention will includecoadministration from days 1 to 21 of a progestational agent, theprogestational agent, preferably levonorgestrel, being administered at adaily dose equal in progestational activity to from about 35 to about100 μg levonorgestrel, and an estrogen, such as ethinyl estradiol, at adaily dose range of from about 10 to about 35 μg. This will be followedon days 22 to 24 by coadministration of an antiprogestin (2 to 50mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose offrom about 10 to about 35 μg. From day 25 to day 28, this regimen may befollowed by no administration or administration of a placebo.

This invention also kits or packages of pharmaceutical formulationsdesigned for use in the regimens described herein. These kits arepreferably designed for daily oral administration over a 28-day cycle,preferably for one oral administration per day, and organized so as toindicate a single oral formulation or combination of oral formulationsto be taken on each day of the 28-day cycle. Preferably each kit willinclude oral tablets to be taken on each the days specified, preferablyone oral tablet will contain each of the combined daily dosagesindicated.

According to the regimens described above, one 28-day kit may comprise:

a) an initial phase of from 14 to 21 daily dosage units of aprogestational agent equal in progestational activity to about 35 toabout 150 μg levonorgestrel, preferably equal in progestational activityto about 35 to about 100 μg levonorgestrel;

b) a second phase of from 1 to 11 daily dosage units of an antiprogestincompound of this invention, each daily dosage unit containing anantiprogestin compound at a daily dosage of from about 2 to 50 mg; and

c) optionally, a third phase of an orally and pharmaceuticallyacceptable placebo for the remaining days of the cycle in which noantiprogestin, progestin or estrogen is administered.

A preferred embodiment of this kit may comprise:

a) an initial phase of 21 daily dosage units of a progestational agentequal in progestational activity to about 35 to about 150 μglevonorgestrel, preferably equal in progestational activity to about 35to about 100 μg levonorgestrel;

b) a second phase of 3 daily dosage units for days 22 to 24 of anantiprogestin compound of this invention, each daily dosage unitcontaining an antiprogestin compound at a daily dosage of from about 2to 50 mg; and

c) optionally, a third phase of 4 daily units of an orally andpharmaceutically acceptable placebo for each of days 25 to 28.

Another 28-day cycle packaging regimen or kit of this inventioncomprises:

a) a first phase of from 18 to 21 daily dosage units of a progestationalagent equal in progestational activity to about 35 to about 150 μglevonorgestrel, preferably equal in activity to from about 35 to about100 μg levonorgestrel, and, as an estrogen, ethinyl estradiol at a dailydose range of from about 10 to about 35 μg; and

b) a second phase of from 1 to 7 daily dosage units of an antiprogestinof this invention at a daily dose of from about 2 to 50 mg; and

c) optionally, an orally and pharmaceutically acceptable placebo foreach of the remaining 0-9 days in the 28-day cycle in which noprogestational agent, estrogen or antiprogestin is administered.

A preferred embodiment of the kit described above may comprise:

a) a first phase of 21 daily dosage units of a progestational agentequal in progestational activity to about 35 to about 150 μglevonorgestrel, preferably equal in activity to from about 35 to about100 μg levonorgestrel, and, as an estrogen, ethinyl estradiol at a dailydose range of from about 10 to about 35 μg; and

b) a second phase of 3 daily dosage units for days 22 to 24 of anantiprogestin administered at a daily dose of from about 2 to 50 mg; and

c) optionally, a third phase of 4 daily dose units of an orally andpharmaceutically acceptable placebo for each of days 25 to 28.

A further 28-day packaged regimen or kit of this invention comprises:

a) a first phase of from 18 to 21 daily dosage units, each containing aprogestational agent of this invention at a daily dose equal inprogestational activity to about 35 to about 150 μg levonorgestrel,preferably equal in activity to from about 35 to about 100 μglevonorgestrel, and ethinyl estradiol at a daily dose range of fromabout 10 to about 35 μg;

b) a second phase of from 1 to 7 daily dose units, each daily dose unitcontaining an antiprogestin of this invention at a concentration of from2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 toabout 35 μg; and

c) optionally, an orally and pharmaceutically acceptable placebo foreach of the remaining 0-9 days in the 28-day cycle in which noprogestational agent, estrogen or antiprogestin is administered.

A preferred embodiment of the package or kit just described comprises:

a) a first phase of 21 daily dosage units, each containing aprogestational agent of this invention at a daily dose equal inprogestational activity to about 35 to about 150 μg levonorgestrel,preferably from about 35 to about 100 μg levonorgestrel, and ethinylestradiol at a daily dose range of from about 10 to about 35 μg;

b) a second phase of 3 daily dose units for days 22 to 24, each doseunit containing an antiprogestin of this invention at a concentration offrom 2 to 50 mg; and ethinyl estradiol at a concentration of from about10 to about 35 μg; and

c) optionally, a third phase of 4 daily units of an orally andpharmaceutically acceptable placebo for each of days 25 to 28.

In each of the regimens and kits just described, it is preferred thatthe daily dosage of each pharmaceutically active component of theregimen remain fixed in each particular phase in which it isadministered. It is also understood that the daily dose units describedare to be administered in the order described, with the first phasefollowed in order by the second and third phases. To help facilitatecompliance with each regimen, it is also preferred that the kits containthe placebo described for the final days of the cycle. It is furtherpreferred that each package or kit comprise a pharmaceuticallyacceptable package having indicators for each day of the 28-day cycle,such as a labeled blister package or dial dispenser packages known inthe art.

In this disclosure, the terms anti-progestational agents,anti-progestins and progesterone receptor antagonists are understood tobe synonymous. Similarly, progestins, progestational agents andprogesterone receptor agonists are understood to refer to compounds ofthe same activity.

These dosage regimens may be adjusted to provide the optimal therapeuticresponse. For example, several divided doses of each component may beadministered daily or the dose may be proportionally increased orreduced as indicated by the exigencies of the therapeutic situation. Inthe descriptions herein, reference to a daily dosage unit may alsoinclude divided units which are administered over the course of each dayof the cycle contemplated.

Compounds of this invention which may be used as the anti-progestationalagents in the kits, methods and regimens herein include those of theFormula I:

wherein:

R¹ and R² are independent substituents selected from the group of H, C₁to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substitutedC₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ toC₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heterocyclic, substituted heterocyclic, COR^(A), or NR^(B)COR^(A);

or R¹ and R² are fused to form:

a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring;

b) an optionally substituted 3 to 8 membered spirocyclic alkenyl; or

c) an optionally substituted 3 to 8 membered heterocyclic ringcontaining one to three heteroatoms from the group including O, S and N;the spirocyclic rings of a), b) and c) being optionally substituted byfrom 1 to 4 groups selected from fluorine, C₁ to C₆ alkyl C₁ to C₆alkoxy, C₁ to C₆ thioalkyl, —CF₃, —OH, —CN, NH₂, —NH(C₁ to C₆ alkyl), or—N(C₁ to C₆ alkyl)₂;

R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R^(B) is H, C₁ to C₃ alkyl or substituted C₁ to C₃ alkyl;

R³ is H, OH, NH₂, C₁ to C₆ alkyl substituted C₁ to C₆ alkyl, C₃ to C₆alkenyl, substituted C₁ to C₆ alkenyl, alkynyl, or substituted alkynyl,COR^(C);

R^(C) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃a aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R⁴ is H, halogen, CN, NO₂, C₁ to C₆ alkyl substituted C₁ to C₆ alkylalkynyl, or substituted alkynyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, amino, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl;

R⁵ is selected from a) or b)

a) R⁵ is a trisubstituted benzene ring containing the substituents X, Yand Z as shown below:

wherein:

X is taken from the group including halogen, CN, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ toC₃ thioalkoxy, substituted C₁ to C₃ thioalkoxy, amino, C₁ to C₃aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3heteroatoms, COR^(D), OCOR^(D), or NR^(E)COR^(D);

R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

Y and Z are independent substituents taken from the group including H,halogen, CN, NO₂, amino, aminoalkyl, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, orC₁ to C₃ thioalkoxy; or

b) R⁵ is a five or six membered ring with 1, 2, or 3 heteroatoms fromthe group including O, S, SO, SO₂ or NR⁶ and containing one or twoindependent substituents from the group including H, halogen, CN, NO₂,amino, and C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl,COR^(F), or NR^(G)COR^(F);

R^(F) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R^(G) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

R⁶ is H or C₁ to C₃ alkyl;

or pharmaceutically acceptable salt thereof.

Preferred anti-progestin compounds of this invention include those ofFormula I:

wherein:

R¹ is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heterocyclic, substituted heterocyclic, COR^(A), or NR^(B)COR^(A);

R² is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, COR^(A), or NR^(B)COR^(A); or

R¹ and R² are fused to form spirocyclic alkyl as a 3 to 8 memberedspirocyclic ring, substituted spirocyclic alkyl constructed by fusing R¹and R² to form a 3 to 8 membered spirocyclic ring, spirocyclic alkenylconstructed by fusing R¹ and R² to form a 3 to 8 membered spirocyclicring, substituted spirocyclic alkenyl constructed by fusing R¹ and R² toform a 3 to 8 membered spirocyclic ring, spirocyclic alkyl constructedby fusing R¹ and R² to form a 3 to 8 membered spirocyclic ring andcontaining one to three heteroatoms from the group including O, S and N;substituted spirocyclic alkyl constructed by fusing R¹ and R² to form a3 to 8 membered spirocyclic ring and containing one to three heteroatomsfrom the group including O, S and N; the spirocyclic rings made byfusing R¹ and R² being optionally substituted by from 1 to 4 groupsselected from fluorine, C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆thioalkyl, —CF₃, —OH, —CN, NH₂, —NH(C₂ to C₆ alkyl), or —N(C₁ to C₆alkyl)₂;

R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R^(B) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

R³ is H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆alkenyl, substituted C₁ to C₆ alkenyl, alkynyl, or substituted alkynyl,COR^(C);

R^(C) is H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, aryl,substituted aryl, C₁ to C₄ alkoxy, substituted C₁ to C₄ alkoxy, C₁ to C₄aminoalkyl, or substituted C₁ to C₄ aminoalkyl;

R⁴ is H, halogen, CN, NO₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl,C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, amino, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl;

R⁵ is a trisubstituted benzene ring containing the substituents X, Y andZ as shown below:

X is taken from the group including halogen, CN, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkoxy, substituted C₁ to C₃ thioalkoxy, amino, C₁to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3heteroatoms, COR^(D), OCOR^(D), or NR^(E)COR^(D);

R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

Y and Z are independent substituents taken from the group including H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ to C₃thioalkoxy; or

R⁵ is a five or six membered ring with 1, 2, or 3 heteroatoms from thegroup including O, S, SO, SO₂ or NR⁶ and containing one or twoindependent substituents from the group including H, halogen, CN, NO₂,amino, and C₁ to C₃ alkyl, or C₁ to C₃ alkoxy;

R⁶ is H, or C₁ to C₃ alkyl;

or pharmaceutically acceptable salt thereof.

Other preferred progesterone receptor antagonist compounds are those ofFormula I

wherein:

R¹=R² and are selected from the group which includes C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, spirocyclic alkyl constructed by fusing R¹and R² to form a 3 to 6 membered spirocyclic ring;

R³ is H, OH, NH₂, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl,COR^(C);

R^(C) is H, C₁ to C₄ alkyl, or C₁ to C₄ alkoxy;

R⁴ is H, halogen, CN, NO₂, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl,C₁ to C₃ alkoxy, or substituted C₁ to C₃ alkoxy;

R⁵ is a disubstituted benzene ring containing the substituents X, and Yas shown below:

X is taken from the group including halogen, CN, C₁ to C₃ alkoxy, C₁ toC₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heterocyclic ringcontaining 1 to 3 heteroatoms, C₁ to C₃ thioalkoxy;

Y is a substituent from the group including H, halogen, CN, NO₂, C₁ toC₃ alkoxy, C₁ to C₄ alkyl, C₁ to C₃ thioalkoxy; or

R⁵ is a five membered ring with the structure:

U is O, S, or NR⁶,

R⁶ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

X′ is from the group including halogen, CN, NO₂, or C₁ to C₃ alkyl andC₁ to C₃ alkoxy, provided that then U is NR⁶, then X′ is not CN;

Y′ is from the group including H and C₁ to C₄ alkyl; or

R⁵ is a six membered ring with the structure:

X¹ is N or CX²;

X² is halogen, CN, alkoxy, or NO₂;

or pharmaceutically acceptable salt thereof.

Further preferred compounds are those of Formula I:

wherein:

R¹=R² and are selected from the group which includes CH₃ and spirocyclicalkyl constructed by fusing R¹ and R² to form a 6 membered spirocyclicring

R³ is H, OH, NH₂, CH₃, substituted methyl, or COR^(C);

R^(C) is H, C₁ to C₃ alkyl, or C₁ to C₄ alkoxy;

R⁴ is H, halogen, NO₂, CN, or C₁ to C₃ alkyl;

R⁵ is a disubstituted benzene ring containing the substituents X and Yas shown below:

X is taken from the group including halogen, CN, methoxy, NO₂, or2-thiazole;

Y is H or F; or

R⁵ is a five membered ring with the structure:

U is O, S, or NH,

X′ is halogen, CN, or NO₂, provided that when U is NR⁶, X is not CN;

Y′ is H or C₁ to C₄ alkyl

and pharmaceutically acceptable salts.

The antiprogestin compounds of this invention may contain an asymmetriccarbon atom and some of the compounds of this invention may contain oneor more asymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in FormulaI, the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having one toeight carbon atoms, preferably one to six carbon atoms; “alkenyl” isintended to include both straight- and branched-chain alkyl group withat least one carbon-carbon double bond and two to eight carbon atoms,preferably two to six carbon atoms; “alkynyl” group is intended to coverboth straight- and branched-chain alkyl group with at least onecarbon-carbon triple bond and two to eight carbon atoms, preferably twoto six carbon atoms.

The terms “substituted alkyl”, “substituted alkenyl”, and “substitutedalkynyl” refer to alkyl, alkenyl, and alkynyl as just described havingfrom one to three substituents selected from the group includinghalogen, CN, OH, NO₂, amino, aryl, heterocyclic, substituted aryl,substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy,alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituentsmay be attached to any carbon of alkyl, alkenyl, or alkynyl groupprovided that the attachment constitutes a stable chemical moiety.

The term “aryl” is used herein to refer to an aromatic system which maybe a single ring or multiple aromatic rings fused or linked together assuch that at least one part of the fused or linked rings forms theconjugated aromatic system. The aryl groups include but not limited tophenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, andphenanthryl.

The term “substituted aryl” refers to aryl as just defined having one tofour substituents from the group including halogen, CN, OH, NO₂, amino,alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substitutedalkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.

The term “heterocyclic” is used herein to describe a stable 4- to7-membered monocyclic or a stable multicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. The N and S atoms may be oxidized. Theheterocyclic ring also includes any multicyclic ring in which any ofabove defined heterocyclic rings is fused to an aryl ring. Theheterocyclic ring may be attached at any heteroatom or carbon atomprovided the resultant structure is chemically stable. Such heterocyclicgroups include, for example, tetrahydrofuran, piperidinyl, piperazinyl,2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl,indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.

The term “substituted heterocyclic” is used herein to describe theheterocyclic just defined having one to four substituents selected fromthe group which includes halogen, CN, OH, NO₂, amino, alkyl, substitutedalkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,or arylthio. The term “alkoxy” is used herein to refer to the OR group,where R is alkyl or substituted alkyl. The term “aryloxy” is used hereinto refer to the OR group, where R is aryl or substituted aryl. The term“alkylcarbonyl” is used herein to refer to the RCO group, where R isalkyl or substituted alkyl. The term “alkylcarboxy” is used herein torefer to the COOR group, where R is alkyl or substituted alkyl. The term“aminoalkyl” refers to both secondary and tertiary amines wherein thealkyl or substituted alkyl groups, containing one to eight carbon atoms,which may be either same or different and the point of attachment is onthe nitrogen atom. The term “halogen” refers to Cl, Br, F, or I.

The antiprogestin compounds of the present invention can be used in theform of salts derived from pharmaceutically or physiologicallyacceptable acids or bases. These salts include, but are not limited to,the following salts with inorganic acids such as hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid and, as the case may be,such organic acids as acetic acid, oxalic acid, succinic acid, andmaleic acid. Other salts include salts with alkali metals or alkalineearth metals, such as sodium, potassium, calcium or magnesium in theform of esters, carbamates and other conventional “pro-drug” forms,which, when administered in such form, convert to the active moiety invivo.

This invention includes pharmaceutical compositions and regimenscomprising one or more pharmacologically active ingredients of thisinvention and a pharmaceutically acceptable carrier or excipient.

When the active compounds of the regimens are employed for the aboveutilities, they may be combined with one or more pharmaceuticallyacceptable carriers or excipients, for example, solvents, diluents andthe like, and may be administered orally in such forms as tablets,capsules, dispersible powders, granules, or suspensions containing, forexample, from about 0.05 to 5% of suspending agent, syrups containing,for example, from about 10 to 50% of sugar, and elixirs containing, forexample, from about 20 to 50% ethanol, and the like, or parenterally inthe form of sterile injectable solutions or suspensions containing fromabout 0.05 to 5% suspending agent in an isotonic medium Suchpharmaceutical preparations may contain, for example, from about 25 toabout 90% of the active ingredient in combination with the carrier, moreusually between about 5% and 60% by weight.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvents customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The antiprogestin compounds of this invention can be prepared followingthe Schemes illustrated below:

As demonstrated in Scheme I, the antiprogestin compounds of thisinvention are generally prepared by employing the suitable couplingreaction as a final step. An appropriately substituted ortho-aminobenzoic acid or its derivatives such as ethyl ester (X=Br, I,, Cl, or alatent coupling precursor such as alkoxy group which can be convertedinto OTf group suitable in the coupling reaction) was treated with asuitable organo metallic reagent, e.g. Grignard reagent, in appropriatenonprotic solvents which include but are not limited to THF or ether togive ortho-amino carbinol 2 under an inert atmosphere such as argon ornitrogen at −78° C. to room temperature. Ring closure of carbinol 2 toyield benzoxazin-2-ones 3 is commonly effected by a condensing agentsuch as carbonyldiimidazole, phosgene, dimethylcarbonate, ordiethylcarbonate in a suitable nonprotic solvent such as THF attemperatures ranging from room temperature to 65° C. The arylation ofbenzoxazin-2-ones 3 to yield 4 can be effected by various couplingreactions including Suzuki, Stille reactions. These reactions arecommonly performed in the presence of transition metallic catalyst,e.g., palladium or nickel complex often with phosphino ligands, e.g.,Ph₃P, 1,1′-bis(diphenylphosphino)ferrocene,1,2-bis(diphenylphosphino)ethane or palladium salt such as palladiumacetate. Under this catalytic condition, an appropriately substitutednucleophilic reagent, e.g., aryl boronic acid, arylstannane, or arylzinc compound, is coupled with benzoxazinones 3 to give 4. If a base isneeded in the reaction, the commonly used bases include but not limitedto sodium bicarbonate, sodium carbonate, potassium phosphate, bariumcarbonate, potassium acetate, or cesium fluoride. The most commonly usedsolvents in these reactions include benzene, DMF, isopropanol, toluene,ethanol, DME, ether, acetone or a mixture of any one of these solventsand water. The coupling reaction is generally executed under an inertatmosphere such as nitrogen or argon at temperatures ranging from roomtemperature to the boiling point of the solvent or solvent system ormixture.

Benzoxazinones 3 can be converted into a nucleophile such as boronicacid which can be coupled with an appropriate electrophile, e.g., arylbromide or aryl iodide, to yield 4 employing the coupling reactioncondition as described above. The transformation of 3 into 5 can beeffected by treating 3 with an organo metallic reagent, e.g., n-BuLi, ina nonprotic solvent such as THF or ether followed by quenching thereaction solution with a suitable electrophile such as trimethyl borate,triisopropyl borate, bishexalkyl tin reagent, or zinc chloride attemperatures ranging from −78° C. to reflux temperature under an inertatmosphere such as argon or nitrogen.

Scheme Ia illustrates an alternative approach leading to thebenzoxazinones 3. Thus, an appropriate aniline 1 is protected with asuitable alkoxy carbonyl protective group including but not limited toallyloxy carbonyl, t-butoxy carbonyl, benzoxy carbonyl, ethoxy carbonyl,or methoxy carbonyl in a suitable solvent such as THF, acetonitrile,with or without presence of a base either as a catalyst or as an acidscavenger. The protected aniline is then treated with a suitable organometallic reagent such as organo lithium agent or Grignard reagent in thesame fashion as to prepare compound 2 to give the carbinol 6. Thetreatment of 6 with a suitable base such as potassium t-butoxide,n-butyl lithium, potassium hydroxide in an appropriate solvent such astoluene, THF, alcohol under an inert atmosphere such as nitrogen orargon at the temperature ranging from room temperature to the boilingpoint of the relevant solvent to afford benzoxazinones 3.

Scheme II describes the procedures to prepare benzoxazinones bearing twodifferent substituents at position-4. The Weinreb amide 8 can beprepared from an appropriately substituted isatoic anhydride 7 whentreated with N-, O-dimethylhydroxyl-amine hydrochloride salt in a proticsolvent such as ethanol, isopropanol at reflux under an inert atmospheresuch as argon or nitrogen. Coupling of amide 8 with an aryl electrophilesuch as aryl boronic acid or arylstannane to give 9 can be effected byemploying a typical coupling reaction such as Suzuki, Stille couplingprocedure in a similar fashion as described for the preparation ofbenzoxazinones 4. Treatment of Weinreb amide 9 with organo metalliccompounds, e.g., alkyllithium, alkynyllithium, aryllithium, or theirGrignard counterpart in a nonprotic solvent such as THF or ether underan inert atmosphere such as argon or nitrogen at −78° C. to roomtemperature affords amino ketone 10. Conversion of ketone 10 to carbinol11 can be effected by treatment of 10 with an organo metallic reagentsuch as alkyl, alkynyl, or aryl Grignard compound in a nonprotic solventsuch as THF or ether under an inert atmosphere such as argon or nitrogenat −78° C. to room temperature. Conversion of ketone 10 to carbinol 11can also be effected by reduction of the ketone group of 10 to thecarbinol moiety of 11 using an appropriate reducing reagent such aslithium aluminum hydride, sodium borohydride in a suitable solvent suchas THF, ether, or anhydrous alcohol under an inert atmosphere in thetemperature ranging from 0° C. to the boiling point of the solvent. Ringclosure of carbinol 11 to produce the compounds of this invention can beaccomplished with condensing agents such as carbonyldiimidazole,phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonproticsolvent such as THF at temperatures ranging from room temperature to 65°C.

Alternatively, ortho-amino ketone 10 can be prepared by treatment ofortho-amino benzonitrile 14 with an organo metallic compound such asorgano lithium reagent or Gringard reagent in a suitable solvent such asTHF or ether under an inert atmosphere such as argon or nitrogen attemperatures ranging from −78° C. to room temperature as illustrated inScheme III. Benzonitrile 14 can be readily prepared from anappropriately substituted benzonitrile such as bromobenzonitrile 13using a suitable coupling reaction such as Stille or Suzuki protocolcarried out in a similar fashion as described for the preparation of theWeinreb amide 9.

Scheme IV depicts an approach to prepare benzoxazinones with a lowperfluoroalkyl substituent at position-4, e.g. R₆ is trifluorormethylgroup. An appropriately substituted chloroaniline 15 was protected witha suitable protective reagent such as pivaloyl chloride or di-tert-butylpyrocarbonate to give protected aniline 16 in a suitable solvent such asacetonitrile, acetone, THF, methylene chloride, or a mixture of solventsuch as methylene chloride and water under an inert atmosphere such asargon or nitrogen at temperatures ranging from 0° C. to 70° C. Asuitable base such as sodium carbonate, sodium bicarbonate, or potassiumcarbonate may be needed when the reaction produces an acid as aside-product such as hydrochloride. Treatment of 16 with an appropriatealkyllithium such as n-butyllithium or s-butyllithium followed byreaction with a low perfluorocarboxy derivatives, e.g., trifluoroacetylchloride, 1-(trifluoroacetyl)-imidazole, or ethyl trifluoroacetate in anonprotic solvent such as ether or THF under an inert atmosphere such asargon or nitrogen at −78° C. to ambient temperature gives the protectiveortho-amino ketones. Subsequent removal of the protecting group can beeffected by reaction of protected amino ketones with a suitable acidsuch as TFA, 3N aqueous hydrochloride solution in a suitable solventsuch as methylene chloride or water at 0° C. to boiling point of thesolvent to afford ortho-amino ketone 17. The preparation of6-chlorobenzoxazinones 19 from 17 can be accomplished in the samefashion as described for the synthesis of benzoxazinone 12 from ketone10. Coupling of 19 with an aryl group to yield the compounds of thisinvention, 12 as shown in scheme IV can be effected by a nickel complexcatalyzed coupling reaction. The palladium catalysts proved not to be anefficient catalyst in this coupling process. The coupling reaction of 19with an appropriate aryl boronic acid can be accomplished in thepresence of a suitable base such as potassium phosphate and a catalystof nickel (0 or II) complex, e.g. a nickel complex of dppe, dppf, ortriphenylphosphine. The most commonly used solvents in the reactioninclude dioxane or THF. The coupling reaction is generally executedunder an inert atmosphere such as nitrogen or argon at temperaturesranging from ambient temperature to 95° C.

As illustrated in scheme V, the antiprogestin compounds 6 or 12 can befurther derivatized at position-1 via numerous approaches leading to avariety of novel cyclocarbamate derivatives including 1-alkyl,1-substituted alkyl, 1-carbonyl, 1-substituted carbonyl, 1-carboxy, andsubstituted 1-carboxy derivatives. For example, alkyl or substitutedalkyl derivatives 20 can be effected by treatment of carbamate 12 or 6with a suitable base such as sodium hydride in suitable solvent such asDMF under an inert atmosphere such as argon or nitrogen followed byaddition of an appropriate electrophile such as alkyl or substitutedalkyl bromide, iodide, or triflate. Such transformation of 12 or 6 atposition-1 can also be effected using biphasic condition as indicated inscheme V in which alkylation is executed using a biphasic catalyst suchas tributylammonium bromide in a suitable solvent such as acetonitrile.A further example of such modification includes but is not limited tothe one depicted in scheme V in that heating of 12 or 6 with triethylorthoformate affords 1-substituted derivatives of compound 12 or 6.

The acylation or carboxylation of the compound 12 or 6 at position-1 togive compound 21 can be readily effected by treatment of 12 or 6 with asuitable acylating or carboxylating reagent such as di-t-butyldicarbonate in the presence of a suitable basic catalyst such as DMAP ina suitable solvent such as acetonitrile under an inert atmosphere suchas argon or nitrogen. The amination of position-1 of compound 12 or 6can be furnished using a suitable aminating reagent such as chloroaminein the presence of a suitable base such as sodium hydride in a suitablesolvent such as THF or diethyl ether following the literature procedure(Metlesics et al. J. Org. Chem. 30, 1311(1965)).

EXAMPLE 1 2-(2-Amino-5-bromophenyl)propan-2-ol

A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF(200 mL) was treated at −78° C. under nitrogen with a solution ofmethylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reactionmixture was slowly warmed to ambient temperature, kept stirring for 48hours under nitrogen and then poured into a cold 0.5 N aqueoushydrochloride solution (300 mL). The mixture was neutralized withaqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) wasadded. The organic layer was separated and aqueous layer was extractedwith ethyl acetate (3×100 mL). The combined organic layers were washedwith brine and dried (MgSO₄). After removal of solvent in vacuo, theresidue was purified by a silica gel flash chromatography (hexane:ethylacetate/3:2) to give 2-(2-amino-5-bromophenyl)propan-2-ol as off-whitesolid (6 g, 57%): mp 62-63° C.; ¹H-NMR (CDCl₃) δ7.19 (d, 1H, J=2.3 Hz),7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.51 (d, 1H, J=8.4 Hz), 4.70 (s, 2H), 1.82(s, 1H), 1.65 (s, 6H).

EXAMPLE 2 6-Bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78 mmol) indry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94 mmol)under nitrogen. The reaction solution was heated at 50° C. overnight.The solvent was removed in vacuo and the residue was dissolved in ethylacetate (100 mL). The solution was washed with 1N aqueous hydrochloridesolution (2×40 mL), brine (20 mL), and dried with MgSO₄. After removalof solvent in vacuo,6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtainedas a white solid (20 g, 100%): mp 199-200° C.; ¹H-NMR (DMSO-d₆) δ10.32(s, 1H, D₂O exchangeable), 7.48 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J=8.5,2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 1.61 (s, 6H).

EXAMPLE 3 6-Iodo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 2-amino-5-iodobenzoic acid following the procedure ofExample 1 and 2. White solid: mp 196-197° C.; ¹H-NMR (DMSO-d₆) δ10.30(s, 1H, D₂O exchangeable), 7.58 (m, 2H), 6.71 (d, 1H, J=8.4 Hz), 1.58(s, 6H). MS (EI) m/z 326 ([M+Na]⁺, 100%). Anal. Calc. For C₁₀H₁₀INO₂: C,39.63; H, 3.33; N, 4.62. Found: C, 39.25; H, 3.24; N, 4.49.

EXAMPLE 4 (1,4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronicacid

To a solution of6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2 g, 7.8mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane(10 M, 2.4 mL, 24 mmol) at −78° C. under nitrogen. After stirring at−78° C. for 30 minutes, a slurry was obtained and treated withtrisopropyl borate (6.5 mL, 28 mmol). The reaction medium was slowlywarmed to ambient temperature and quenched with 1N aqueous hydrochloricacid solution (60 mL). Ethyl acetate (100 mL) was added and organiclayer was separated, and aqueous layer was extracted with ethyl acetate(3×60 mL). The combined organic layer was washed with brine and driedwith MgSO₄. The solvent was removed in vacuo and the residue waspurified by a silica gel flash chromatography (ethyl acetate:hexane/2:1)to afford (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronicacid as a white solid (1.4 g, 81%): mp 249-250° C.; ¹H-NMR (DMSO-d₆)δ10.21 (s, 1H, D₂O exchangeable), 7.90-7.95 (br s, 2H, D₂Oexchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8 Hz), 1.61 (s, 6H); MS(ESI) m/z 222 ([M+H]⁺, 87%).

EXAMPLE 56-(3-Chlorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one(Procedure A)

A mixture of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(1.5 g, 5.9 mmol), 3-chlorophenyl boronic acid (1.83 g, 11.7 mmol),tetrakis(triphenylphosphine)-palladium (0) (0.35 g, 0.3 mmol), andsodium carbonate (2.48 g, 23.4 mmol) in a mixture of DME and water (40mL/10 mL) was degassed to remove the oxygen and then heated at 85° C.under a blanket of nitrogen for 3 hours. The reaction mixture was cooledto ambient temperature and quenched with a saturated aqueous ammoniumchloride solution (20 mL). Ethyl acetate (50 mL) was added and organiclayer was separated. The aqueous layer was extracted with ethyl acetate(3×15 mL). The combined organic layers were washed with brine and driedwith MgSO₄. The solvent was removed in vacuo and the residue waspurified by a silica gel flash chromatography (hexane:ethyl acetate/2:1)to afford6-(3-chlorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one asa yellowish solid (1.4 g, 82%): mp 158-159° C.; ¹H-NMR (DMSO-d₆) δ10.31(s, 1H, D₂O exchangeable), 7.75 (s, 1H), 7.61 (m, 3H), 7.46 (t, 1H,J=7.9 Hz), 7.39 (dd, 1H, J=7.0, 1.1 Hz), 6.96 (d, 1H, J=8.6 Hz), 1.68(s, 6H); Anal. Calc. For C₁₆H₁₄ClNO₂.0.1 H₂O: C, 66.37; H, 4.94; N,4.84. Found: C, 66.14; H, 4.61; N, 4.71.

EXAMPLE 66-(3-Methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

Prepared according to Procedure A from6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and3-methoxyphenyl boronic acid. Yellow solid: mp 164-165° C.; ¹H-NMR(DMSO-d₆) δ10.3 (s, 1H), 7.56 (m, 2H), 7.36 (t, 1H, J=7.89 Hz), 7.20 (m,2H), 6.96 (d, 1H, J=8.88 Hz), 6.91 (dd, 1H, J=8.13, 2.35 Hz), 3.8 (s,3H), 1.7 (s, 6H); MS (ESI) m/z 284 ([M+H]⁺, 30%); Anal. Calc. ForC₁₇H₁₇NO₃: C, 72.07; H, 6.05; N, 4.94. Found: C, 70.58; H, 5.73; N, 4.67

EXAMPLE 76-(2-Chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared according to Procedure A from6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and2-chlorophenyl boronic acid. White solid: mp 181-182° C.; MS (ESI) m/z288 ([M+H]⁺, 70%); Anal. Calc. For C₁₆H₁₄ClNO₂: C, 66.79, H, 4.90; N,4.87. Found: C, 66.78; H, 4,82; N, 4.55

EXAMPLE 86-(4-Chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

Prepared according to Procedure A from6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and4-chlorophenyl boronic acid. White solid: mp 255-257° C.; ¹H-NMR(DMSO-d₆) δ10.3 (s, 1H), 7.7 (d, 2H, J=8.52 Hz), 7.55 (m, 2H), 7.5 (d,2H, J=8.52 Hz), 6.96 (d, 1H, J=8.52 Hz), 1.7 (s, 6H); MS (ESI) m/z 288([M+H]⁺, 70%); Anal. Calc. For C₁₆H₁₄ClNO₂: C, 66.79; H, 4.90; N, 4.87.Found: C, 66.34; H, 4.76; N, 4.75

EXAMPLE 96-(3-Chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (seeexample 35, 0.15 g, 0.61 mmol) in anhydrous methanol was added sodiumborohydride (0.07 g, 1.03 mmol) at room temperature (rt) under nitrogen.After 15 minutes, the reaction mixture was treated with ice-water. Ethylacetate (30 mL) was added, organic layer was separated, and aqueouslayer was extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine (10 mL) and dried over MgSO₄. Afterremoval of solvent, the residue obtained was crystallized from tolueneto afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanol as white solid(0.087 g, 58%): ¹H-NMR (DMSO-d₆) δ7.55 (t, 1H, J=1.4 Hz), 7.50 (d, 1H,J=7.8 Hz), 7.44 (d, 1H, J=2.1 Hz), 7.39 (t, 1H, J=8.2 Hz), 7.31-7.21 (m,2H), 6.68 (d, 1H, J=8.1 Hz), 5.25 (s, 2H), 5.20 (m, 1H), 4.83 (m, 1H),1.35 (d, 3H, J=8.8 Hz); MS (EI) m/z 247 (M⁺).

A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanol (0.03 g, 0.13mmol) and triphosgene (0.01 g, 0.04 mmol) in dry THF (3 mL) was stirredunder a blanket of nitrogen for 10 minutes. The solvent was removed togive 6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneas a white solid (0.031 g, 91%): mp 155-156° C.; ¹H-NMR (DMSO-d₆) δ10.3(s, 1H), 7.72 (m, 1H), 7.62 (m, 2H), 7.56 (m, 1H), 7.47 (t, 1H, J=8.00Hz), 7.39 (d, 1H, J=8.0 Hz), 6.98 (d, 1H, J=8.0 Hz), 5.50 (q, 1H, J=6.82Hz), 1.6 (d, 3H, J=6.82 Hz); MS (APCI) m/z 274 ([M+H]⁺, 100%)

EXAMPLE 106-(3-Chloro-phenyl)-4-ethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared according to the procedure of Example 9 from1-(4-amino-3′-chloro-biphenyl-3-yl)-propanol and triphosgene. Whitesolid: mp 146-148° C.; ¹H-NMR (DMSO-d₆) δ10.3 (s, 1H), 7.70 (m, 1H),7.60 (m, 3H), 7.47 (t, 1H, J=8.22 Hz), 7.39 (d, 1H, J=8.28 Hz), 6.97 (d,1H, J=8.22 Hz), 5.4 (t, 1H, J=10.9 Hz), 1.9 (m, 2H), 0.97 (t, 3H, J=7.68Hz); MS (ESI) m/z 286 ([M−H]⁻, 100%)

EXAMPLE 116-(3-Chloro-phenyl)-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-benzyl alcohol andtriphosgene according to the procedure of Example 9. Off-white solid: mp177-178° C.; ¹H-NMR (DMSO-d₆) δ10.5 (s, 1H), 7.68 (dd, 1H, J=8.7, 1.7Hz), 7.62 (t, 1H, J=1.74 Hz), 7.54-7.5 (m, 1H), 7.48-7.34 (m, 8H), 7.04(d, 1H, J=8.7 Hz), 6.6 (s, 1H); MS (ESI) m/z 336 ([M+H]⁺, 30%)

EXAMPLE 123-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile(Procedure B)

A mixture of(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid(2.22 g, 10 mmol), 3-bromobenzonitrile (2.18 g, 12 mmol),tetrakis(triphenylphosphine)palladium (0) (0.6 g, 0.52 mmol), and sodiumcarbonate (2.2 g, 21 mmol) in a mixture of DME and water (70 mL/15 mL)was degassed to remove the oxygen and then heated at 85° C. under ablanket of nitrogen for 3 hours. The reaction mixture was cooled toambient temperature and quenched with a saturated aqueous ammoniumchloride solution (20 mL). Ethyl acetate (100 mL) was added and organiclayer was separated. The aqueous layer was extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine and driedwith MgSO₄. The solvent was removed in vacuo and the residue waspurified by a silica gel flash chromatography (hexane:ethyl acetate/1:1)to give3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrileas an off-white solid (0.7 g, 25%): mp 236-237° C.; ¹H-NMR (DMSO-d₆)δ10.34 (s, 1H, D₂O exchangeable), 8.21 (s, 1H), 8.02 (d, 1H, J=8.1 Hz),7.79 (d, 1H, J=7.7 Hz), 7.60-7.70 (m, 3H), 6.98 (d, 1H, J=8.2 Hz), 1.71(s, 6H); Anal. Calc. For C₁₇H₁₄N₂O₂.0.1 H₂O: C, 72.89; H, 5.11; N,10.00. Found: C, 72.75; H, 5.05; N, 9.65.

EXAMPLE 134,4-Dimethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Prepared from 6-iodo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneand 3-nitrophenyl boronic acid according to Procedure A. Yellowishsolid: mp 244-245° C.; ¹H-NMR (DMSO-d₆) δ10.38 (s, 1H, D₂Oexchangeable), 8.47 (s, 1H), 8.14-8.20 (m, 2H), 7.70-7.76 (m, 3H), 7.01(d, 1H, J=8.1 Hz), 1.68 (s, 6H); MS (EI) m/z 297 ([M−H]⁻, 100%). Anal.Calc. For C₁₆H₁₄N₂O₄: C, 64.42; H, 4.73; N, 9.39. Found: C, 63.93; H,4.91; N, 8.71

EXAMPLE 146-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and1,3-dibromo-5-fluorobenzene following Procedure B. White solid: mp182-183° C.; ¹H-NMR (DMSO-d₆) δ10.36 (s, 1H, D₂O exchangeable), 7.78 (s,1H), 7.58-7.65 (m, 3H), 7.49 (dd, 1H, J=8.3, 1.8 Hz), 6.96 (d, 1H, J=8.5Hz), 1.69 (s, 6H); ¹⁹F-NMR (DMSO-d₆) δ−112.46 (m, 1F); MS (CI) m/z 352([M+H]⁺, 78%), 350 ([M+H]⁺, 75%). Anal. Calc. For C₁₆H₁₃BrFNO₂: C,54.88; H, 3.74; N, 4.00. Found: C, 54.83; H, 3.82; N, 3.95

EXAMPLE 153-(4.4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile

A mixture of6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-2H-benz[d][1,3]oxazin-2-one (1g, 2.8 mmol), zinc cyanide (0.2 g, 1.7 mmol), andtetrakis(triphenylphosphine)-palladium (0) (0.2 g, 0.17 mmol) in dry DMF(20 mL) was degassed to remove oxygen and then was heated at 85° C.under a blanket of nitrogen for 6.5 hours. The reaction solution wascooled to room temperature and poured onto a cold saturated aqueousammonium chloride solution (100 mL). The white precipitate appeared andwas collected on a filter. The white solid was washed with the distilledwater (3×20 mL) and dissolved in a mixture of ethyl acetate (10 mL) andmethanol (10 mL). The solution was applied on a pad of silica gel andeluted with a mixture of ethyl acetate and hexane (1:1). Afterevaporation,3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrilewas obtained as a white solid (0.7 g, 84%): mp 253-254° C.; ¹H-NMR(DMSO-d₆) δ10.4 (s, 1H, D₂O exchangeable), 8.13 (s, 1H), 7.92 (m, 1H),7.82 (m, 1H), 7.73 (m, 2H), 6.98 (d, 1H, J=8.2 Hz), 1.68 (s, 6H);¹⁹F-NMR (DMSO-d₆) δ−112.25 (m, 1F); MS (EI) m/z 296 (M⁺, 65%); Anal.Calc. For C₁₇H₁₃FN₂O₂: C, 68.91; H, 4.42; N, 9.45. Found: C, 68.85; H,4.58; N, 9.14.

EXAMPLE 165-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-nicotinonitrile

Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromo-5-cyanopyridine according to Procedure B.Off-white solid: mp 290-291° C.; ¹H-NMR (DMSO-d₆) δ10.41 (s, 1H, D₂Oexchangeable), 9.21 (d, 1H, J=2.2 Hz), 8.97 (d, 1H, J=1.7 Hz), 8.68 (t,1H, J=2.1 Hz), 7.76 (m, 2H), 7.01 (d, 1H, J=8.2 Hz), 1.70 (s, 6H); MS(ESI) m/z 278 (M−H, 96%). Anal. Calc. For C₁₆H₁₃N₃O₂.0.2 H₂O: C, 67.94;H, 4.77; N, 14.85. Found: C, 68.04; H, 4.70; N, 14.58.

EXAMPLE 174-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and4-bromo-2-thiophenecarbonitrile according to Procedure B. Yellowishsolid: mp 230-231° C. (decomposed); ¹H-NMR (CDCl₃) δ8.32 (s, 1H, D₂Oexchangeable), 7.83 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.4 Hz), 7.43 (dd,1H, J=8.2, 1.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=8.2 Hz), 1.78(s, 6H); MS (EI) m/z 283(M−H, 100%). Anal. Calc. For C₁₅H₁₂N₂O₂S.0.2H₂O: C, 62.57; H, 4.34, N, 9.73. Found: C, 62.48; H, 4.31; N, 9.64.

EXAMPLE 18 5-Bromo-2-thiophenecarbonitrile

A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol),hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), andethanol (500 mL) was heated under nitrogen at reflux for two hours. Thereaction mixture was cooled to ambient temperature and concentrated invacuo to give an oil. The crude product was triturated twice with icewater and the solid obtained was collected on a filter. A mixture of aportion of the above solid (44.31 g, 215 mmol), copper (II) acetatemonohydrate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated atreflux for three hours. The solvent was removed in vacuo and the residuewas dissolved in ethyl acetate. The solution was washed with 5% aqueoussulfuric acid (2×30 mL), water (2×30 mL), brine (20 mL), and dried(MgSO₄). The solvent was removed in vacuo and the residue was dissolvedin a minimum amount of chloroform (1 L) and allowed to crystallize. Thecrystal obtained was collected on a filter and the filtrate wasconcentrated and purified by a chromatography (silica gel, chloroform)to give the title compound as an off-white solid (31.5 g combined, 58%).IR (film) cm⁻¹ 2200. ¹H-NMR (CDCl₃) δ7.39-7.38 (d, 1H, J=4.1 Hz), 7.10(d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M⁺, 98%) 189(M⁺, 100%).

EXAMPLE 19 5-Bromo-4-methyl-2-thiophene carboxaldehyde

To a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400mL) was added at −40° C. under nitrogen a solution of n-BuLi (2.5 M, 153mL, 0.383 mol) in hexane. After addition, the solution was stirred at−40° C. under nitrogen for 30 minutes, cooled to −78° C. and treateddropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol)in anhydrous THF (450 mL). The reaction solution was stirred at −78° C.for 30 minutes and treated with anhydrous DMF (100 mL). The mixture wasallowed to warm to ambient temperature and was quenched with 1N aqueoushydrochloride solution (1 L). The solution was extracted with ethylacetate(3×450 mL). The extracts were washed with water, brine and dried(MgSO₄). After removal of solvent in vacuo, the title compound wasobtained as a white solid (46 g, 88.3%). A sample of the product wascrystallized from hexane: mp 63-65° C.; IR (KBr) 1654 cm⁻¹. ¹H-NMR(CDCl₃) δ9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z 204/206(M⁺). Anal. Calc. For C₆H₅BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H,2.44.

EXAMPLE 20 5-Bromo-4-methyl-2-thiophenecarbonitrile

Prepared from 5-bromo-4-methyl-2-thiophene carboxaldehyde using theprocedure of Example 18. White solid: mp 40-42° C.; IR (KBr) 2200 cm⁻¹;¹H-NMR (CDCl₃) δ7.29 (s, 1H), 2.21 (s, 3H). MS (EI) m/z 201/203 (M⁺,98%/100%); Anal. Calc. For C₆H₄BrNS: C, 35.66; H, 1.99; N, 6.93. Found:C, 36.00; H, 2.14; N, 6.76.

EXAMPLE 215-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile

Prepared according to Procedure B from 5-bromo-2-thiophenecarbonitrileand (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid.Off-white solid: mp 264-266° C. ¹H-NMR (DMSO-d₆) δ10.3 (s, 1H), 7.97 (d,1H, J=7.9 Hz), 7.60-7.66 (m, 3H). 6.96 (d, 1H, J=8.1 Hz), 1.65 (S, 6H).MS (APCI) m/z 285 (M+H)⁺, 302 (M+NH₄)⁺. Anal. Calc. For C₁₅H₁₂N₂O₂S: C,63.36; H, 4.25; N, 9.85. Found: C, 63.01; H, 4.36; N, 9.39.

EXAMPLE 225-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-methyl-thiophene-2-carbonitrile

Prepared according to Procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and5-bromo-4-methyl-2-thiophenecarbonitrile. Off-white solid: mp 195-200°C. ¹H-NMR (DMSO-d₆) δ10.2 (s, 1H), 8.32 (s, 1H), 7.41-7.44 (m, 2H), 7.01(d, 1H, J=8.8 Hz), 2.28 (s, 3H), 1.64 (s, 6H); MS (APCI) m/z 299 [M+H]⁺.Anal. Calc. For C₁₆H₁₄N₂O₂S; C, 64.41; H, 4.75; N, 8.89. Found: C,64.64; H, 4.62; N, 9.39.

EXAMPLE 234-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and4-bromo-2-furancarbonitrile according to Procedure B. Off-white solid:mp 255-256° C. ¹H-NMR (DMSO-d₆) δ10.32 (s, 1H, D₂O exchangeable), 8.57(s, 1H), 8.15 (s, 1H), 7.61 (s, 1H), 7.55 (dd, 1H, J=8.3, 1.5 Hz), 6.92(d, 1H, J=8.2 Hz), 1.65 (s, 6H); MS (ESI) m/z 269(M+H, 72%). Anal. Calc.For C₁₅H₁₂N₂O₃: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.14; H, 4.59;N, 10.07.

EXAMPLE 244,4-Diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-oneand 3-nitrophenyl boronic acid according to Procedure A. Off-whitesolid: mp 193-194° C. ¹H-NMR (CDCl₃) δ9.19 (s, 1H, D₂O exchangeable),8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H,J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z325 ([M−H]⁻, 100%). Anal. Calc. For C₁₈H₁₈N₂O₄.0.3 H₂O: C, 65.17; H,5.65; N, 8.44. Found: C, 65.31; H, 5.60; N, 8.10.

EXAMPLE 256-(3-Chlorophenyl)-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-oneand 3-chlorophenyl boronic acid according to Procedure A. White solid:mp 150-151° C. ¹H-NMR (CDCl₃) δ8.52 (s, 1H, D₂O exchangeable), 7.50 (s,1H), 7.31-7.44 (m, 4H), 7.16 (d, 1H, J=1.5 Hz), 6.89 (d, 1H, J=8.2 Hz),2.03 (m, 4H), 0.94 (t, 6H, J=7.4 Hz); MS (EI) m/z 315(M⁺, 53%). Anal.Calc. For C₁₈H₁₈ClNO₂: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.16; H,5.81; N, 4.32.

EXAMPLE 26 1-(2-Amino-5-bromo-phenyl)cyclohexanol

Prepared according to the procedure of Example 1 from2-amino-5-bromobenzoic acid and the Grignard reagent prepared from1,5-dibromopentane. A clear oil: ¹H-NMR (DMSO-d₆) δ7.07 (d, 1H, J=2.3Hz), 7.03 (dd, 1H, J=8.4, 2.4 Hz), 6.55 (d, 1H, J=8.6 Hz), 5.49 (s, 2H,D₂O exchangeable), 5.00 (s, 1H, D₂O exchangeable), 2.01 (d, 2H, J=1.8Hz), 1.66-1.77 (m, 2H), 1.44-1.61 (m, 4H), 1.16-1.34 (m, 2H). MS (ESI)m/z 270/272 ([M+H]⁺, 98%/100%).

EXAMPLE 27 6-Bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2-(1H)-one

Prepared from 1-(2-amino-5-bromo-phenyl)cyclohexanol and carbonyldiimidazole according to the procedure of Example 2. Off-white solid: mp208-210° C. ¹H-NMR (DMSO-d₆) δ10.26 (s, 1H), 7.45 (d, 1H, J=2.2 Hz),7.39 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=8.3 Hz), 1.90-1.97 (m, 2H),1.80-1.85 (m, 5H), 1.25-1.35 (m, 1H); MS (APCI) m/z 296 ([M+H]⁺, 68%)

EXAMPLE 28Spiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronicacid

Prepared according to the procedure of Example 4 from6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2-(1H)-one. Off-whitesolid: mp 223-225° C. ¹H-NMR (DMSO-d₆) δ10.17 (s, 1H, D₂O exchangeable),7.92 (s, 2H, D₂O exchangeable), 7.67 (s, 1H), 7.63 (dd, 1H, J=8.0, 1.1Hz), 6.81 (d, 1H, J=7.9 Hz), 1.96 (s, 1H), 1.93 (s, 1H), 1.57-1.88 (m,7H), 1.24-1.34 (m, 1H); MS (ESI) m/z 262 (M+H)⁺.

EXAMPLE 296-(3-Chlorophenyl)-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2-(1H)-one

Prepared according to Procedure A from6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and3-chlorophenyl boronic acid. Off-white solid: mp 165-168° C. ¹H-NMR(DMSO-d₆) δ10.25 (s, 1H), 7.74 (t, 1H, J=1.9 Hz), 7.50-7.67 (m, 3H),7.42-7.49 (m 1H), 7.35-7.38 (m, 1H), 6.93-6.95 (d, 1H, J=4.2 Hz),1.91-1.98 (m, 4H), 1.64-1.76 (m, 3H), 1.60 (m, 2H), 1.29-1.39 (m, 1H);MS (APCI) m/z 328 ([M+H]⁺, 80%)

EXAMPLE 30 6-Bromo-spiro-[4H-3,1-benzoxazine-4,1′-cyclopentane]-2-(1H)-one

Prepared according to the procedure of Example 26 and 27 from2-amino-5-bromobenzoic acid and the Grignard reagent prepared from1,4-dibromobutane. Off-white solid: mp 180-185° C. ¹H-NMR (DMSO-d₆)δ10.29 (s, 1H, D₂O exchangeable), 7.45 (d, 1H, J=2.2 Hz), 7.41 (dd, 1H,J=8.1, 2.1 Hz), 6.82 (d, 1H, J=8.0 Hz), 1.96-2.09 (m, 4H), 1.76-1.87 (m,4H); MS (EI) m/z 281 (M⁺, 98%). Anal. Calc. For C₁₂H₁₂BrNO₂: C, 51.08;H, 4.29; N, 4.96. Found: C, 50.53; H, 4.21; N, 4.85

EXAMPLE 316-(3-Chlorophenyl)-spiro-[4H-3,1-benzoxazine-4,1′-cyclopentane]-2(1H)-one

Prepared from6-bromo-spiro-[4H-3,1-benzoxazine-4,1′-cyclopentane]-2-(1H)-one and3-chlorophenyl boronic acid according to Procedure A. Off-white solid:mp 140-145° C. ¹H-NMR (DMSO-d₆) δ10.27 (s, 1H), 7.75 (t, 1H, J=1.8 Hz),7.53-7.63 (m, 3H), 7.44 (t, 1H, J=7.9 Hz), 7.36 (m, 1H), 6.95 (d, 1H,J=8.6 Hz), 2.09-2.15 (m, 4H), 1.81-1.89 (m, 4H). MS (ESI) m/z 314[M+H]⁺. Anal. Calc. For C₁₈H₁₆ClNO₂: C, 68.90; H, 5.14; N, 4.46. Found:C, 60.94; H, 4.94; N, 3.78.

EXAMPLE 326-(3-Nitrophenyl)-spiro[4H-3,1-benzoxazine-4,1′-cyclohexan]-2(1H)-one

Prepared from6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp245-246° C. ¹H-NMR (CDCl₃) δ8.39 (t, 1H, J=1.9 Hz), 8.20 (dd, 1H, J=8.2,1.4 Hz), 8.11 (s, 1H, D₂O exchangeable), 7.86 (d, 1H, J=8.0 Hz), 7.62(t, 1H, J=8.1 Hz), 7.50 (dd, 1H, J=8.2, 1.9 Hz), 7.39 (d, 1H, J=1.8 Hz),6.93 (d, 1H, J=8.2 Hz), 2.25 (d, 2H, J=12.7 Hz), 1.60-1.99 (m, 7H),1.31-1.42 (m, 1H); MS (EI) m/z 337 ([M−H]⁻, 100%). Anal. Calc. ForC₁₉H₁₈N₂O₄.0.35H₂O: C, 66.21; H, 5.47; N, 8.13. Found: C, 66.22; H,5.43; N, 7.86.

EXAMPLE 33 2-Amino-5-bromo-N-methoxy-N-methylbenzamide

To a mixture of N, O-dimethylhydroxylamine hydrochloride (9.42 g, 96mmol) and triethyl amine (13.5 mL, 96 mmol) in ethanol and water (100mL/10 mL) was added a solution of 5-bromoisatoic anhydride (20 g, 74mmol) in ethanol and water (100 mL/10 mL) at ambient temperature undernitrogen. The reaction mixture was heated at reflux for 3 hours. Thesolvent was removed in vacuo and the residue was dissolved in ethylacetate (100 mL), washed with 1N aqueous sodium hydroxide solution (2×20mL), brine (30 mL), and dried with MgSO₄. After removal of solvent, theresidue was purified by a silica gel flash chromatography (hexane:ethylacetate/3:2) to give 2-amino-5-bromo-N-methoxy-N-methylbenzamide as anoff-white solid (13 g, 68%): mp 80-81° C.; ¹H-NMR (CDCl₃) δ7.49 (d, 1H,J=2.1 Hz), 7.26 (dd, 1H, J=8.3, 2.0 Hz), 6.59 (d, 1H, J=8.4 Hz), 4.69(br, 2H), 3.58 (s, 3H), 3.34 (s, 3H); Anal. Calc. For C₉H₁₁BrN₂O₂: C,41.72; H, 4.28; N, 10.81. Found: C, 41.99; H, 4.16; N, 10.82.

EXAMPLE 34 4-Amino-3′-chloro-biphenyl-3-carbonitrile

Prepared from 2-amino-5-bromobenzonitrile and 3-chlorophenyl boronicacid according to procedure A. Off-white solid: mp 118-119° C.; ¹H-NMR(DMSO-d₆) δ7.80 (d, 1H, J=2.3 Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J=8.0Hz), 7.42 (t, 1H, J=7.9 Hz), 7.31 (m, 1H), 6.87 (d, 1H, J=8.7 Hz), 6.29(br, 2H); Anal. Calc. For C₁₃H₉ClN₂: C, 68.28; H, 3.97; N, 12.25. Found:C, 67.68; H, 4.06; N, 11.89.

EXAMPLE 35 1-(4-Amino-3′-chloro-biphenyl-3-yl)-ethanone

A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30mmol), 3-chlorophenyl boronic acid (5.63 g, 36 mmol),tetrakis(triphenylphosphine)palladium (0) (1.73 g, 1.5 mmol), and sodiumcarbonate (7.63 g, 72 mmol) in a mixture of DME and water (150 mL/30 mL)was degassed to remove the oxygen and heated at 85° C. under nitrogenfor 3 hours. The reaction mixture was cooled to room temperature andtreated with brine (30 mL) and ethyl acetate (100 mL). The organic layerwas separated and aqueous layer was extracted with ethyl acetate (3×40mL). The combined organic layers were washed with brine and dried withMgSO₄. After removal of solvent, the residue was purified by a flashchromatography (silica gel, hexane:ethyl acetate/1:1) to give5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g,57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THFwas added in a dropwise fashion a solution of methyllithium in ether(1.4M, 28.6 mL, 40 mL) at −78° C. under nitrogen. After stirred for 30minutes, the reaction mixture was treated with a saturated aqueousammonium chloride solution (50 mL) at −78° C. Ethyl acetate (100 mL) wasadded, organic layer was separated, and aqueous layer was extracted withethyl acetate (3×20 mL). The combined organic layers were washed (brine)and dried (MgSO₄). After removal of solvent, the residue was purified bya flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone as a yellow solid (2 g,47%): mp 89-90° C.; ¹H-NMR (CDCl₃) δ7.89 (d, 1H, J=2.0 Hz), 7.51 (m,2H), 7.25-7.40 (m, 3H), 6.73 (d, 1H, J=8.6 Hz), 6.38 (br, 2H), 2.65 (s,3H); MS (EI) m/z 268([M+Na]⁺, 60%); Anal. Calc. For C₁₄H₁₂ClNO: C,68.44; H, 4.92; N, 5.70. Found: C, 68.40; H, 4.89; N, 5.61.

EXAMPLE 364-Allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(Procedure C)

To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (0.2 g,0.82 mmol) in anhydrous THF (10 mL) was added a solution ofallylmagnesium bromide in ether (1.0 M, 3 mL, 3 mmol) at 0° C. undernitrogen. The reaction solution was slowly warmed to ambient temperatureand stirred under nitrogen for 1 hour. A saturated aqueous ammoniumchloride solution (10 mL) was added, followed by addition of ethylacetate (50 mL). The organic layer was separated and aqueous layer wasextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine and dried with MgSO₄. After removal of solvent, theresidue was purified by flash chromatography (silica gel, hexane:ethylacetate/3:1) to afford amino carbinol intermediate which was used innext step without further purification. To a solution of above aminocarbinol in anhydrous THF was added CDI (0.38 g, 2.3 mmol) at ambienttemperature under nitrogen. The reaction solution was heated at 55° C.for 12 hours and then cooled to room temperature. The solvent wasremoved in vacuo and the residue was purified by flash chromatography(silica gel, hexane:ethyl acetate/2:1) to yield4-allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneas a white solid (130 mg from two steps, 52%): mp 128-129° C.; ¹H-NMR(CDCl₃) δ8.68 (s, 1H, D₂O exchangeable), 7.50 (s, 1H), 7.44 (dd, 1H,J=8.2, 1.9 Hz), 7.31-7.40 (m, 3H), 7.25 (d, 1H, J=1.6 Hz), 6.92 (d, 1H,J=8.2 Hz), 5.70-5.85 (m, 1H), 5.17 (m, 2H), 2.76 (m, 2H), 1.79 (s, 3H);MS (ESI) m/z 314 ([M+H]⁺, 40%); Anal. Calc. For C₁₈H₁₆ClNO₂: C, 68.90;H, 5.14; N, 4.46. Found: C, 68.90; H, 5.18; N, 4.43.

EXAMPLE 376-(3-Chlorophenyl)-4-methyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone andpropynyl-magnesium bromide followed by treatment with CDI according toProcedure C. White solid: mp 184-185° C.; ¹H-NMR (CDCl₃) δ8.18 (s, 1H,D₂O exchangeable), 7.53 (t, 1H, J=1.7 Hz), 7.49 (s, 1H), 7.31-7.48 (m,4H), 6.92 (d, 1H, J=8.1 Hz), 2.02 (s, 3H), 1.87 (s, 3H); MS (ESI) m/z304 ([M−H]⁻, 100%); Anal. Calc. For C₁₈H₁₄ClNO₂: C, 69.35; H, 4.53; N,4.49. Found: C, 69.19; H, 4.37; N, 4.41.

EXAMPLE 386-(3-Chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (0.2 g, 0.82mmol) and ethynylmagnesium bromide followed by treatment with CDIaccording to procedure C. Off-white solid: mp 185-186° C.; ¹H-NMR(CDCl₃) δ8.18 (s, 1H, D₂O exchangeable), 7.53 (t, 1H, J=1.7 Hz), 7.49(s, 1H), 7.31-7.48 (m, 4H), 6.92 (d, 1H, J=8.1 Hz), 2.81 (s, 1H), 1.87(s, 3H); MS (ESI) m/z 304 ([M−H]⁻, 100%); Anal. Calc. For C₁₇H₁₂ClNO₂:C, 68.58; H, 4.06; N, 4.70. Found: C, 68.24; H, 3.94; N, 4.65.

EXAMPLE 396-(3-Chlorophenyl)-4-methyl-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (0.2 g, 0.82mmol) and phenylmagnesium bromide followed by treatment with CDIaccording to Procedure C. White solid: mp 179-180° C.; ¹H-NMR (CDCl₃)δ8.27 (s, 1H, D₂O exchangeable), 7.51-7.57 (m, 2H), 7.28-7.45 (m, 9H),6.92 (d, 1H, J=8.4 Hz), 2.12 (s, 3H); MS (ESI) m/z 348 ([M−H]⁻, 100%);Anal. Calc. For C₂₁H₁₆ClNO₂: C, 72.10; H, 4.61; N, 4.00. Found: C,71.72; H, 4.86; N, 3.91.

EXAMPLE 404-Benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-benzyl-ethanol(prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone andbenzylmagnesium bromide according to Procedure C, 0.14 g, 0.42 mmol) andtriphosgene (0.04 g, 0.14 mmol) in dry THF (10 mL) was stirred under ablanket of nitrogen for 10 minutes. Upon completion of the reaction, theTHF was removed and the residue purified via flash chromatography(silica gel, 35% ethyl acetate/hexane) to give4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.045 g, 30%) as an off-white solid: mp 187-188° C.; ¹H-NMR (DMSO-d₆)δ10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53(m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m,3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3 Hz),3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H); MS (ESI) m/z 364 ([M+H]⁺, 100%);Anal. Calc. For C₂₂H₁₈ClNO₂: C, 72.63; H, 4.99; N, 3.85. Found: C,71.82; H, 5.09; N, 3.58.

EXAMPLE 416-(3-Chloro-phenyl)-4-cyclopropyl-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a solution of cyclopropylmagnesium bromide in anhydrous THF (preparedfrom cyclopropyl bromide and magnesium metal, 70 mmol) at 52° C. wasadded under nitrogen 4-amino-3′-chloro-biphenyl-3-carbonitrile (5.2 g,22.7 mmol). The reaction mixture was stirred at 52° C. for 1 hour,cooled to rt, and quenched with 1N aqueous HCl solution (100 mL). Ethylacetate (100 mL) was added and the aqueous layer extracted with ethylacetate (3×40 mL). The combined organic layers were washed with brineand dried over MgSO₄. The solvent was removed and the residue waspurified via silica gel column (hexane:ethyl acetate/20:1) to give the(4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone: ¹H-NMR(hydrogen chloride salt, DMSO-d₆) δ8.30 (d, 1H, J=2.1 Hz), 7.76 (t, 1H,J=1.7 Hz), 7.68-7.63 (m, 2H), 7.43 (t, 1H, J=7.9 Hz), 7.32 (m, 1H), 6.88(d, 1H, J=8.7 Hz), 4.50 (bs, 3H), 3.07 (m, 1H), 0.98 (m, 4H); MS((+)ESI) m/z 272/274 (M⁺).

To a solution of (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone(0.67 g, 2.5 mmol) in anhydrous THF (10 mL) at −78° C. was added asolution of methylmagnesium bromide (3.0 M in diethyl ether, 2.5 mL, 7.5mmol) under nitrogen. The reaction mixture was slowly warmed to rt,stirred under nitrogen for 12 hours, and quenched with a saturatedaqueous ammonium chloride solution (40 mL). Ethyl acetate (50 mL) wasadded, organic layer was separated, and dried (MgSO₄). After removal ofsolvent, the residue was purified via silica gel column (hexane:ethylacetate/7:1) to afford1-(4-amino-3-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol as yellow oil:MS (EI) m/z 287/289 (M⁺).

The title compound was prepared from1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol and1,1′carbonyldiimidazole according to Procedure C. Off-white solid: mp158-159° C.; ¹H-NMR (DMSO-d₆) δ10.3 (s, 1H), 7.74 (t, 1H, J=1.71 Hz),7.67-7.57 (m, 3H), 7.47 (t, 1H, J=7.88 Hz), 7.39 (d, 1H, J=8.1 Hz), 6.95(d, 1H, J=8.12 Hz), 1.7 (s, 3H), 1.45 (m, 1H), 0.48 (m, 2H), 0.28 (m,2H); MS (APCI) m/z 314 ([M+H]⁺, 100%); Anal. Calc. For C₁₈H₁₆ClNO₂: C,68.9; H, 5.14; N, 4.46. Found: C, 68.13; H, 5.01; N, 4.36.

EXAMPLE 426-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

1-(4-Amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanolwas prepared from(4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone andpropynylmagnesium bromide according to Example 41.

A mixture of1-(4-amino-3-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol(0.02 g, 0.064 mmol) and 1,1′-carbonyldiimidazole (0.016 g, 0.096 mmol)in dry THF (10 mL) was stirred under a blanket of nitrogen for 10minutes. Upon completion of the reaction, the THF was removed and theresidue purified via flash chromatography (silica gel, 40% ethylacetate/hexane) to give6-(3-chlorophenyl)-4-cyclopropyl-4-prop-1-ynyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.014 g, 56%) as a light yellow solid: mp 178-179° C.; ¹H-NMR (DMSO-d₆)δ10.6 (s, 1H), 7.68 (m, 2H), 7.64 (bs, 1H), 7.59 (d, 1H, J=7.72 Hz),7.49 (t, 1H, J=7.82 Hz), 7.42 (d, 1H, J=7.95 Hz), 7.02 (d, 1H, J=8.0Hz), 1.86 (s, 3H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H); MS (ESI)m/z 336 ([M−H]⁻, 100%).

EXAMPLE 436-(3-Chloro-phenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

(4-Amino-3′-chloro-biphenyl-3-yl)-dicylopropyl-methanol (mp 90-92° C.;MS ((+)ESI) m/z 314 (M+H)⁺.) was prepared from(4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone andcyclopropylmagnesium bromide according to Example 41.

The title compound was prepared according to Example 41 from(4-amino-3′-chloro-biphenyl-3-yl)-dicylopropyl-methanol and1,1′-carbonyldiimidazole. Yellow solid: mp 198-200° C.; ¹H-NMR (DMSO-d₆)δ10.3 (s, 1H), 7.72 (bs, 1H), 7.67 (bs, 1H), 7.62 (m, 2H), 7.48 (t, 1H,J=7.88 Hz), 7.40 (d, 1H, J=8.04 Hz), 6.94 (d, 1H, J=8.27 Hz), 1.55 (m,2H), 0.5 (m, 6H), 0.28 (m, 2H); MS (EI) m/z 339 (M⁺, 40%); Anal. Calc.For C₂₀H₁₈ClNO₂: C, 70.69; H, 5.34 N, 4.12. Found: C, 69.38; H, 5.07; N,4.02.

EXAMPLE 446-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Following the procedure of Example 41,(4-amino-3′-chloro-biphenyl-3-yl)-propynyl-methanone (mp 112-114° C.; MS((+) ESI) m/z 270/272 (M+H)⁺) was treated with propynylmagnesium bromideto give (4-amino-3-chloro-biphenyl-3-yl)-dipropynyl-methanol which wasreacted with 1,1′-carbonyldiimidazole to afford the title compound.Yellow solid: mp 151° C. (decomposed); ¹H-NMR (DMSO-d₆) δ10.8 (s, 1H),7.71 (dd, 1H, J=8.52, 1.94 Hz), 7.69 (m, 2H), 7.61 (d, 1H, J=7.64 Hz),7.50 (t, 1H, J=7.85 Hz), 7.43 (d, 1H, J=7.99 Hz), 7.06 (d, 1H, J=8.23Hz), 2.0 (s, 6H); MS (APCI) m/z 336 ([M+H]⁺, 20%).

EXAMPLE 456-(3-Bromo-5-fluorophenyl)-1,4,4-trimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one

To a solution of6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one(0.34 g, 0.99 mmol) in dry DMF (10 mL) was added under nitrogen at roomtemperature sodium hydride (80 mg, 2.0 mmol) in one portion. The mixturewas stirred at ambient temperature for 30 minutes, treated withiodomethane (1 mL, excess), and stirred for 2 hours. To the reactionmixture was added a cold saturated ammonium chloride solution (30 mL)and the white precipitate obtained was collected on a filter, washedwith the distilled water to afford the title compound as a white solid(0.31 g, 87%): mp 157-158° C.; ¹H-NMR (DMSO-d₆) δ7.83 (s, 1H), 7.76 (dd,1H, J=8.5, 2.0 Hz), 7.67 (m, 2H), 7.53 (dt, 1H, J=8.3, 1.9 Hz), 7.18 (d,1H, J=8.5 Hz), 3.33 (s, 3H), 1.67 (s, 6H); ¹⁹F-NMR (DMSO-d₆) δ−111.01(m, 1F); MS (APCI) m/z 364 ([M+H]⁺, 96%), 366 ([M+H]⁺, 100%).

EXAMPLE 46 1-(2-Amino-5-chloro-phenyl)-2,2,2-tifluoro-ethanone

To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (6.7 g, 30mmol) in anhydrous THF (100 mL) under nitrogen at 0° C. was added asolution of n-BuLi (2.5M, 30 mL, 70 mmol) in hexane in a dropwisefashion. After addition, the solution was kept stirring at 0° C. for 40minutes and treated with a solution of 1-(trifluoroacetyl)imidazole (9mL, 78 mmol) in anhydrous THF (10 mL). The reaction mixture was warmedto ambient temperature and kept for 18 hours. To the reaction solutionwas added a saturated aqueous ammonium chloride solution (50 mL)followed by addition of ethyl acetate (100 mL). The organic layer wasseparated and the solvent was removed in vacuo. The residue obtained wassuspended in 3N aqueous hydrochloride solution (50 mL) and heated atreflux overnight. The reaction solution was cooled to room temperatureand treated with a cold ammonium hydroxide solution to pH>8. The aqueousmixture was extracted with ethyl acetate (3×50 mL) and organic layerswere washed with brine and dried (MgSO₄). After removal of solvent, theresidue was purified by a flash chromatography (silica gel,hexane:ethylacetate/4:1) to afford the title compound as a yellow solid(1 g, 15%): mp 93-94° C.; ¹H-NMR (CDCl₃) δ7.70 (m, 1H), 7.33 (dd, 1H,J=9.0, 2.3 Hz), 6.70 (d, 1H, J=9.1 Hz), 6.45 (bs, 2H); MS (ESI) m/z 222(M−H, 100%), 224 (M−H, 33%).

EXAMPLE 476-Chloro-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 1-(2-amino-5-chloro-phenyl)-2, 2, 2-trifluoro-ethanone byaddition of methylmagnesium bromide followed by treatment of theresultant carbinol with 1,1′-carbonyldiimidazole according to theprocedure of Example 2. White solid: mp 216-216° C.; ¹H-NMR (DMSO-d₆)δ10.91 (bs, 1H, D₂O exchangeable), 7.64 (d, 1H, J=1.6 Hz), 7.49 (dd, 1H,J=8.6, 2.3 Hz), 6.95 (d, 1H, J=8.6 Hz), 1.91 (s, 3H); ¹⁹F-NMR (DMSO-d₆)δ−82.0 (s, 1F); MS (EI) m/z 264 ([M−H]⁻, 100%), 266 ([M−H]⁻, 33%). Anal.Calc. For C₁₀H₇ClF₃NO₂: C, 45.22; H, 2.66; N, 5.27. Found: C, 45.32, H,2.77; N, 4.83.

EXAMPLE 486-(3-Methoxyphenyl)-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A mixture of6-chloro-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one(0.2 g, 0.75 mmol), 3-methoxyphenyl boronic acid (0.13 g, 0.9 mmol),potassium phosphate (0.23 g, 1.1 mmol), and nickel (II)(diphenylphosphino)ferrocenyl dichloride (52 mg, 0.076 mmol) inanhydrous dioxane was subject to a blanket of nitrogen to remove oxygenand heated at 95° C. under nitrogen for 48 hours. Another portion of3-methoxyphenyl boronic acid (0.13 g, 0.9 mmol) and Nickel (II)(diphenylphosphino)ferrocenyl dichloride (52 mg, 0.076 mmol) was addedand the reaction solution was heated at 95° C. under nitrogen for afurther 48 hours. The reaction solution was cooled to room temperature.Saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate(50 mL) was added. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (3×20 mL). The combined organic layerwas washed with brine and dried (MgSO₄). After removal of solvent, theresidue was purified by a flash chromatography (silica gel, hexane:ethylacetate/4:1) to afford the title compound as a white solid (50 mg, 20%):mp 178-179° C.; ¹H-NMR (DMSO-d₆) δ10.85 (bs, 1H, D₂O exchangeable), 7.73(m, 2H), 7.38 (t, 1H, J=7.9 Hz), 7.23 (d, 1H, J=7.7 Hz), 7.19 (d, 1H,J=1.9 Hz), 7.02 (d, 1H, J=8.2 Hz), 6.94 (dd, 1H, J=8.2, 2.4 Hz), 3.88(s, 3H), 1.98 (s, 3H); ¹⁹F-NMR (DMSO-d₆) δ−81.88 (s, 1F); Anal. Calc.For C₁₇H₁₄F₃NO₃: C, 60.54; H, 4.18; N, 4.15. Found: C, 60.58; H, 4.44;N, 4.19.

EXAMPLE 497-(3-Methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

A mixture of 7-chloro-4,4′-dimethylbenzoxazin-2-one (0.197 g, 0.93mmol), 3-methoxyphenyl boronic acid (0.21 g, 1.4 mmol), Ni(dppf)Cl₂(0.095 g, 0.14 mmol), and potassium phosphate (0.59 g, 2.79 mmol) indioxane (10 mL) was subject to a blanket of nitrogen for 15 minutes at50° C. and then was heated at 95° C. for 48 hours. The reaction mixturewas cooled to room temperature and ethyl acetate (100 mL) was added. Theorganics were washed twice with aqueous ammonium chloride (30 mL), oncewith brine (30 mL), and dried over magnesium sulfate. The residue waspurified via flash chromatography (silica gel, 40% ethyl acetate/hexane)to give7-(3-methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.090 g, 35%) as a clear oil. The oil was triturated with ether (25 ml)to furnish a white solid: mp 167-168° C.; ¹H-NMR (DMSO-d₆) δ10.3 (s,1H), 7.42-7.28 (m, 3H), 7.14 (d, 1H, J=8.11 Hz), 7.11 (bs, 2H), 6.96(dd, 1H, J=8.11 Hz), 3.56 (s, 3H), 1.52 (s, 6H); MS (EI) m/z 283([M+H]⁺, 90%); Anal. Calc. For C₁₇H₁₇NO₃: C, 72.07; H, 6.05; N, 4.94.Found: C, 71.59; H, 6.08; N, 4.79.

EXAMPLE 506-(3-Acetyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile(0.25 g, 0.9 mmol) was dissolved in THF (10 mL) and cooled to 0° C. Tothis solution, methylmagnesium bromide (3.0 M in ether, 1.8 mL, 5.4mmol) was added and the reaction mixture was heated to reflux undernitrogen. Upon completion of the reaction, the reaction mixture wasquenched with 1 N aqueous HCl solution after cooling to rt. The mixturewas extracted with ethyl acetate (100 mL), dried over MgSO₄ andconcentrated. Purification of the residue obtained via chromatography(silica gel, 50% ethyl acetate/hexane) gave6-(3-acetyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneas a white solid (0.031 g, 12%): mp 178-179° C.; ¹H-NMR (CDCl₃) δ8.15(t, 1H, J=1.71 Hz), 8.04 (s, 1H), 7.95 (dt, 1H, J=8.85, 1.13 Hz), 7.76(dt, 1H, J=7.90, 1.43 Hz), 7.57 (t, 1H, J=7.72 Hz), 7.52 (dd, 1H,J=8.28, 2.11 Hz), 7.39 (d, 1H, J=1.81 Hz), 6.93 (d, 1H, J=8.19 Hz), 2.69(s, 3H), 1.81 (s, 6H); MS (EI) m/z 295 ([M+H]⁺, 40%)

EXAMPLE 516-(3-Benzoyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

Prepared from3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrileand phenylmagnesium bromide according to the procedure of Example 50. Awhite solid: mp 156-157° C.; ¹H-NMR (DMSO-d₆) δ10.33 (s, 1H), 8.0-7.96(m, 2H), 7.80 (m, 2H), 7.73-7.56 (m, 7H), 6.99 (d, 1H, J=8.06 Hz), 1.67(s, 6H); MS (EI) m/z 357 ([M+H]⁺, 40%); Anal. Calc. For C₂₃H₁₉NO₃: C,77.29; H, 5.36; N, 3.92 Found: C, 75.7; H, 5.28; N, 3.86

EXAMPLE 524,4-Dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydrobenzo[d][1,3]oxazin-2-one

A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile (0.77 g, 2.8 mmol), trimethylsilylazide (0.68 g, 5.6 mmol), and dibutyl tin oxide (0.071 g, 0.28 mmol) indioxane (20 mL) was heated at reflux under a blanket of nitrogen. Uponcompletion of the reaction, the dioxane was removed, the organics takenup in ethyl acetate (100 mL), and washed with NaHCO₃ (100 mL). Theaqueous layer was acidified with 1 N aqueous HCl and extracted withethyl acetate (100 mL). The organic layer was dried over MgSO₄, andconcentrated. Crystallization from ether (20 mL) gave4,4-dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydrobenzo[d][1,3]-oxazin-2-oneas a light yellow solid (0.23 g, 26%): mp 238-240° C.; ¹H-NMR (DMSO-d₆)δ10.4 (s, 1H), 8.3 (bs, 1H), 8.02 (d, 1H, J=7.66 Hz), 7.9 (d, 1H, J=7.91Hz), 7.72-7.65 (m, 3H), 7.03 (d, 1H, J=8.75 Hz), 1.70 (s, 6H); MS (ESI)m/z 320 ([M−H]⁻, 100%); Anal. Calc. For C₁₇H₁₅N₅O₂: C, 63.54; H, 4.71;N, 21.79. Found: C, 62.16; H, 4.67; N, 21.31.

EXAMPLE 534-(4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile

(4,4-Dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acidwas prepared from 2-amino-5-bromobenzoic acid according to Example 1, 2,and 4. A white solid: mp 240-242° C.; ¹H-NMR (DMSO-d₆) δ10.13 (s, 1H),8.01 (s, 2H), 7.85 (s, 1H), 7.64 (d, 1H, J=7.9 Hz), 6.77 (d, 1H, J=7.9Hz), 1.38 (m, 2H), 0.52 (m, 2H), 0.39 (m, 4H), 0.22 (m, 2H).

The title compound was prepared according to Procedure B from(4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acidand 4-bromo-2-thiophene carbonitrile. A white solid: mp 244-245° C.;¹H-NMR (DMSO-d₆) δ10.25 (s, 1H), 8.49 (d, 1H, J=0.87 Hz), 8.33 (s, 1H),7.74 (d, 1H, J=1.44 Hz), 7.67 (dd, 1H, J=8.28, 1.54 Hz), 6.90 (d, 1H,J=8.28 Hz), 1.53 (m, 2H), 0.59-0.41 (m, 6H), 0.31-0.24 (m, 2H); MS (ESI)m/z 335 ([M−H]⁻, 100%); Anal. Calc. For C₁₉H₁₆N₂O₂S: C, 67.84; H, 4.79;N, 8.33. Found: C, 64.92; H, 4.66; N, 7.71.

EXAMPLE 546-(3-Bromo-5-fluoro-phenyl)-4,4-dicyclopropyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one

Prepared according to Procedure B from(4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acidand 1,3-dibromo-5-fluorobenzene. A white solid: mp 228-229° C.; ¹H-NMR(DMSO-d₆) δ10.3 (s, 1H), 7.76-7.72 (m, 2H), 7.65 (dd, 1H, J=8.32, 1.74Hz), 7.60 (d, 1H, J=10.36 Hz), 7.51 (d, 1H, J=8.3 Hz), 6.93 (d, 1H,J=8.31 Hz), 1.63-1.54 (m, 2H), 0.58-0.41 (m, 6H), 0.30-0.28 (m, 2H); MS(APCI) m/z 402/404 ([M−H]⁻, 100%); Anal. Calc. For C₂₀H₁₇BrFNO₂: C,58.48; H, 4.17; N, 3.41. Found: C, 58.77; H, 4.23; N, 3.32.

EXAMPLE 553-(4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile

A mixture of6-(3-bromo-5-fluoro-phenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo-[d][1,3]oxazin-2-one(0.4 g, 1.0 mmol), Zn(CN)₂ (0.71 g, 0.61 mmol), andtetrakis(triphenylphosphine)-palladium (0) (0.07 g, 0.06 mmol) in DMF(20 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C.and then was heated at 85° C. for 1 hour. After cooling to roomtemperature, the reaction mixture was poured into NH₄Cl (100 mL) andextracted with ethyl acetate (3×50 mL). The organic layers were washedwith brine, dried over MgSO₄, and concentrated. The clear oil obtainedwas triturated with ether (30 ml) to give a white solid.Recrystallization of the solid from ethyl acetate gave3-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile(0.016 g, 4.6%): mp 250-252° C.; ¹H-NMR (DMSO-d₆) δ10.3 (s, 1H), 8.12(s, 1H), 7.97 (d, 1H, J=10.54 Hz), 7.81-7.79 (m, 2H), 7.73 (dd, 1H,J=8.3, 1.59 Hz), 6.94 (d, 1H, J=8.34 Hz), 1.59 (m, 2H), 0.58-0.42 (m,6H), 0.30-0.28 (m, 2H); MS (ESI) m/z 347 ([M−H]⁻, 100%); Anal. Calc. ForC₂₁H₁₇FN₂O₂: C, 72.4; H, 4.92; N, 8.04 Found: C, 72.4; H, 4.74; N, 7.61

EXAMPLE 566-(3-Bromo-5-methyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one

Prepared from(4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and3,5-dibromotoluene according to Procedure B. White solid: mp 231-233°C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.66 (s, 1H), 7.58-7.56 (m, 2H),7.50 (s, 1H), 7.37 (s, 1H), 6.95 (d, 1H, J=8.67 Hz), 2.37 (s, 3H), 1.67(s, 6H); MS (ESI) m/z 344/346 ([M−H]⁻, 100%); Anal. Calc. ForC₁₇H₁₆BrNO₂: C, 58.98; H, 4.66; N, 4.05. Found: C, 58.82; H, 4.62; N,3.94.

EXAMPLE 576-(3-Bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-one

Prepared from(4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and1,3-dibromo-5-trifluoromethoxybenzene according to Procedure B. Whitesolid: mp 214-216° C.; 1H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.99 (s, 1H),7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97 (d, 1H, J=8.0 Hz), 1.68 (s, 6H);MS (ESI) m/z 414 ([M−H]⁻, 100%); Anal. Calc. For C₁₇H₁₃BrF₃NO₃: C,49.06; H, 3.15; N, 3.37. Found: C, 49.16; H, 3.05; N, 3.30.

EXAMPLE 583-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methyl-benzonitrile

Prepared from6-(3-bromo-5-methyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-oneaccording to the procedure of example 55. White solid: mp 256-258° C.;¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.67-7.62(m, 3H), 6.97 (d, 1H, J=8.11 Hz), 2.42 (s, 3H), 1.68 (s, 6H); MS (APCI)m/z 293 ([M+H]⁺, 100%); Anal. Calc. For C₁₈H₁₆N₂O₂: C, 73.96; H, 5.52;N, 9.58. Found: C, 73.26; H, 5.46; N, 9.24.

EXAMPLE 593-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-trifluoromethoxy-benzonitrile

Prepared from6-(3-bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-oneaccording to the procedure of example 55. White solid: mp 227-228° C.;¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.97 (s,1H), 7.75-7.72 (m, 3H), 6.99(d, 1H, J=8.11 Hz), 1.7 (s, 6H); MS (APCI)m/z 363 ([M+H]⁺, 80%); Anal. Calc. For C₁₈H₁₃F₃N₂O₃: C, 59.67; H, 3.62;N, 7.73. Found: C, 59.63; H, 3.55; N, 7.58.

EXAMPLE 606-(3,5-difluoro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one

Prepared according to procedure B from(4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and1-bromo-3,5-difluorobenzene. A white solid: mp 218-219° C.; ¹H-NMR(DMSO-d₆) δ10.4 (s, 1H), 7.67-7.65 (m, 2H), 7.49 (d, 2H, J=7.73 Hz),7.19 (t, 1H, J=9.29 Hz), 6.96 (d, 1H, J=8.88 Hz), 1.7 (s, 6H); MS (APCI)m/z 290 ([M+H]⁺, 100%); Anal. Calc. For C₁₆H₁₃F₂NO₂: C, 66.43; H, 4.53,N, 4.84. Found: C, 66.01; H, 4.46; N, 4.67.

EXAMPLE 616-(3,5-dichloro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneand 3,5-dichlorophenyl boronic acid according to Procedure A. A whitesolid: mp 245-246° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.77 (m, 2H),7.67-7.64 (m, 2H), 7.56 (bs, 1H), 6.96 (d, 1H, J=7.98 Hz), 1.7 (s, 6H);MS (EI) m/z 321 ([M+H]⁺, 40%); Anal. Calc. For C₁₆H₁₃Cl₂NO₂: C, 59.32;H, 4.11; N, 4.32. Found: C, 59.13; H, 4.29; N, 4.17.

EXAMPLE 626-(3,5-Bis-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneand bis-trifluoromethylphenyl boronic acid according to Procedure A. Awhite solid: mp 258-260° C.; 1H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.35 (s,2H), 8.05 (s, 1H), 7.79-7.76 (m, 2H), 7.01 (d, 1H, J=8.01 Hz), 1.7 (s,6H); MS (ESI) m/z 390 ([M+H]⁺, 20%); Anal. Calc. For C₁₈H₁₃F₆NO₂: C,55.54; H, 3.37; N, 3.6. Found: C, 55.5; H, 3.54; N, 3.47.

EXAMPLE 633-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methoxy-benzonitrile

A mixture of(4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (4.2g, 19.0 mmol), 3-cyano-5-methoxyphenyltriflate (5.1 g, 19.0 mmol),tetrakis(triphenylphosphine)-palladium (0) (1.1 g, 0.95 mmol), sodiumcarbonate (4.0 g, 38.0 mmol), and lithium bromide (5 g, 57 mmol) in DME(50 mL) and water (25 mL) was subject to a blanket of nitrogen for 15minutes at 50° C. and then was heated at 85° C. for 1 hour. The reactionwas cooled to room temperature and ethyl acetate (100 mL) was added. Theorganic layers were washed twice with aqueous ammonium chloride (100 mL)and once with brine (100 mL), dried over magnesium sulfate andconcentrated. Purification via chromatography (silica gel, 40% ethylacetate/hexane) gave3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methoxy-benzonitrileas a white solid (0.69 g, 53%): mp 254-255° C.; ¹H-NMR (DMSO-d₆) δ10.4(s, 1H), 7.84 (s, 1H), 7.67-7.61 (m, 2H), 7.55 (bs, 1H), 7.4 (bs 1H)6.99 (d, 1H, J=7.94 Hz), 3.88 (s, 3H), 1.67 (s, 6H); MS (EI) m/z 308([M+H]⁺, 30%); Anal. Calc. For C₁₈H₁₆N₂O₃: C, 68.13; H, 5.40; N, 8.83.Found: C, 68.03; H, 5.22; N, 8.46.

EXAMPLE 646-(3-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1-bromo-3-fluorobenzene according to Procedure A. A light yellow solid:mp 181-182° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.62-7.44 (m, 5H), 7.16(t, 1H, J=2.22 Hz), 6.97 (d, 1H, J=8.83), 1.67 (s, 6H); MS (EI) m/z 271([M+H]⁺, 40%); Anal. Calc. For C₁₆H₁₄FNO₂: C, 69.91; H, 5.3; N, 5.1.Found: C, 70.0; H, 5.32; N, 4.92.

EXAMPLE 656-(3-Chloro-4-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 1-bromo-3-chloro-4-fluorobenzene according toProcedure A. White solid: mp 211-212° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s,1H), 7.92 (dd, 1H, J=7.13, 2.19 Hz), 7.71-7.66 (m, 1H), 7.60-7.57 (m,2H), 7.49 (t, 1H, J=8.95 Hz), 6.96 (d, 1H, J=8.01 Hz), 1.67 (s, 6H); MS(EI) m/z 305 ([M+H]⁺, 20%); Anal. Calc. For C₁₆H₁₃CIFNO₂: C, 62.86; H,4.29; N, 4.58. Found: C, 62.52; H, 4.45; N, 4.42.

EXAMPLE 663-(1-Diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5fluoro-benzonitrile

A mixture of3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6yl)-5-fluoro-benzonitrile(0.25 g, 0.84 mmol) and triethylorthoformate (50 mL) was heated at 160°C. for 12 hours. The excess triethylorthoformate was removed in vacuoand purification via chromatography (silica gel, 20% ethylacetate/hexane) gave3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile(0.116 g, 33%) as a white solid: mp 123-124° C.; ¹H-NMR (DMSO-d₆) δ7.97(d, 1H, J=8.68 Hz), 7.66 (bs, 1H), 7.53-7.44 (m, 2H), 7.35-7.32 (m, 2H),6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.73-3.61 (m, 2H), 1.77 (s, 6H), 1.27(t, 6H, J=7.05 Hz); MS (ESI) m/z 295 ([M−H]⁺, 100%, lower MW ionconsistent with loss of diethyl acetal); Anal. Calc. For C₂₂H₂₃FN₂O₄: C,66.32; H, 5.82; N, 7.03. Found: C, 65.89; H, 5.92; N, 6.66.

EXAMPLE 673-Fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzol[d][1,3]oxazin-6-yl)-benzonitrile

A solution of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile (0.150 g, 0.51 mmol) in DMF (5mL) was treated at rt with sodium hydride (0.061 g, 1.53 mmol). Themixture was stirred for 30 minutes and treated with chloromethylmethylether (0.062 g, 7.7 mmol). Upon completion of the reaction, thereaction mixture was quenched with water (25 mL) and extracted withethyl acetate (3×30 mL), dried over MgSO₄, and concentrated. The residuewas purified via chromatography (silica gel, 25% ethyl acetate/hexane)to give3-fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrileas a white solid (0.11 g, 65%): mp 169-171° C.; ¹H-NMR (DMSO-d₆) δ8.17(bs, 1H), 8.03 (dt, 1H, J=10.4, 2.13 Hz), 7.85-7.77 (m, 3H), 7.31 (d,1H, J=8.49 Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H); MS (APCI) m/z341 ([M+H]⁺, 50%); Anal. Calc. For C₁₉H₁₇FN₂O₃: C, 65.32; H, 5.19; N,8.02. Found: C, 64.92; H, 4.96; N, 7.73.

EXAMPLE 68 Phosphoric acid6-(3-cyano-5fluoro-phenyl)-4,4-dimethyl-4H-benzo[d][1.3]oxazin-2-ylester diethyl ether

To a solution of3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile(0.25 g, 0.84 mmol) in DMF (5 mL) was added sodium hydride (60% in oil,0.101 g, 2.53 mmol). After stirring for 30 minutes, the reaction mixturewas treated with diethyl chlorophosphate (0.22 mL, 1.52 mmol). Uponcompletion of the reaction, the reaction solution was quenched withwater (25 mL) and the product extracted with ethyl acetate (2×50 mL),dried over MgSO₄, and concentrated. The residue was purified viachromatography (silica gel, 25% ethyl acetate/hexane) to give phosphoricacid6-(3-cyano-5-fluoro-phenyl)-4,4-dimethyl-4H-benzo[d][1,3]oxazin-2-ylester diethyl ether as a white solid (0.064 g, 18%): mp 196-198° C.;¹H-NMR (DMSO-d₆) δ8.19 (bs, 1H), 8.05 (d, 1H, J=10.4 Hz), 7.9-7.8 (m,3H), 7.51 (d, 1H, J=8.41 Hz), 4.33-4.41 (m, 4H), 1.76 (s, 6H), 1.27 (t,6H, J=7.05 Hz); MS (APCI) m/z 433 ([M+H]⁺, 80%); Anal. Calc. ForC₂₁H₂₂FN₂O₅P: C, 58.33; H, 5.13; N, 6.48. Found: C, 58.1; H, 5.11; N,6.25.

EXAMPLE 693-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-fluoro-benzonitrile

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and5-bromo-2-fluorobenzonitrile according to Procedure B. white solid: mp229-230° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.15 (dd, 1H, J=7.39, 2.12Hz), 7.95-7.89 (m, 1H), 7.59-7.48 (m, 3H), 6.99 (d, 1H, J=8.1 Hz), 1.7(s, 6H); MS (APCI) m/z 297 ([M+H]⁺, 100%); Anal. Calc. For C₁₇H₁₃FN₂O₂:C, 68.91; H, 4.42; N, 9.45. Found: C, 68.74; H, 4.83; N, 9.10.

EXAMPLE 70 8-Fluoro-4,4-dimethyldihydro-benzo[d][1,3]oxazin-2-one

N-(tert-Butoxycarbonylamino)-3-fluorobenzoic acid (Takagishi et al.Synlett 4, 360-2 (1992); mp 159-161° C.) was deprotected usingtrifluoroacetic acid to give o-amino benzoic acid which was treated withmethylmagnesium bromide to afford o-amino dimethyl carbinol. The o-aminodimethyl carbinol (2.23 g, 13.2 mmol) was treated with1,1-carbonyldiimidizole (2.8 g, 17.2 mmol) in THF (20 mL) at 50° C. for12 hours. Upon completion of reaction, it was cooled to rt and ethylacetate (100 mL) added. The organic layer was washed with 10% aqueousHCl solution (2×25 mL), dried over MgSO₄ and concentrated. The residuewas purified via chromatography (silica gel, 10% ethyl acetate/hexane)to give 8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one as awhite solid (1.3 g, 50%): mp 127-128° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s,1H), 7.22-7.12 (m, 2H), 7.07-7.00 (m, 2H), 1.6 (s, 6H); MS (APCI) m/z196 ([M+H]⁺, 100%); Anal. Calc. For C₁₀H₁₀FNO₂: C, 61.53; H, 5.16; N,7.18. Found: C, 61.27; H, 5.37; N, 7.02.

EXAMPLE 716-(3-Chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-one

To a solution of 8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one(0.15 g, 0.77 mmol) in acetic acid (5 mL) was added dropwise a solutionof bromine (0.37 g, 2.31 mmol) in acetic acid (5 mL) under nitrogen atrt. After stirring for 10 minutes, the mixture was concentrated and theresidue obtained was purified by a silica gel column (hexane:ethylacetate/4:1) to afford6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one as anoff-white solid (0.176 g, 84%) which was used in next step withoutfurther purification.

A mixture of6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one (0.176g, 0.64 mmol), 4-fluoro-3-chlorophenyl boronic acid (0.15 g, 0.84 mmol),tetrakis(triphenylphosphine)-palladium (0) (0.04 g, 0.032 mmol), andsodium carbonate (0.20 g, 1.92 mmol) in DME (10 mL) and water (5 mL) wassubject to a blanket of nitrogen for 15 minutes at 50° C. and then washeated at 85° C. for 1 hour. The reaction mixture was cooled to roomtemperature and ethyl acetate (100 mL) was added. The organic layer waswashed twice with aqueous ammonium chloride (100 mL) and once with brine(100 mL), dried over magnesium sulfate and concentrated. The residue waspurified via chromatography (silica gel, 25% ethyl acetate/hexane) togive6-(3-chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-oneas a white solid (0.13 g, 66%): mp 246-248° C.; ¹H-NMR (DMSO-d₆) δ10.5(s, 1H), 8.00 (dd, 1H, J=7.09, 2.32 Hz), 7.78-7.73 (m, 1H), 7.62 (dd,1H, J=11.86, 1.77 Hz), 7.7 (t, 2H, J=9 Hz), 1.7 (s, 6H); MS (APCI) m/z324 ([M+H]⁺, 100%); Anal. Calc. For C₁₆H₁₂F₂NO₂ 0.5 H₂O C, 57.76; H,3.94; N, 4.21. Found: C, 57.49; H, 3.69; N, 4.03.

EXAMPLE 726-(3-Bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1,3-dibromobenzene according to procedure B. A white solid: mp 174-175°C.; ¹H-NMR (DMSO-d₆) δ10.35 (s, 1H), 7.88 (bs, 1H), 7.68 (d, 1H, J=7.5Hz), 7.6-7.51 (m, 3H), 7.4 (t, 1H, J=7.5 Hz), 6.97 (d, 1H, J=8.57 Hz),1.64 (s, 6H); MS (EI) m/z 331([M⁺], 60%), 333([M⁺], 60%); Anal. Calc.For C₁₆H₁₄BrNO₂: C, 57.85; H, 4.25; N, 4.22. Found: C, 57.7; H, 4.36; N,4.09.

EXAMPLE 734,4-Dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A mixture of6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol),tetrakis(triphenylphosphine) palladium (0) (0.17 g, 0.24 mmol), andcuprous (I) iodide (0.05 g, 0.28 mmol) in triethyl amine (20 mL) washeated under nitrogen at 80° C. for 3 hours. The reaction mixture wascooled to rt and the solvent was removed. The residue was taken up inethyl acetate (50 mL) and washed with 1N aqueous HCl (3×20 mL) and brine(20 mL). The organic layer was separated and dried (MgSO₄). Afterremoval of solvent, the residue was purified by a silica gelchromatography (hexane:ethyl acetate/3:1) to afford the title compoundas a white solid (0.77 g, 92%): mp 240-242° C.; ¹H-NMR (DMSO-d₆) δ10.3(s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96(d, 1H, J=7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349([M⁺],50%); Anal. Calc. For C₂₁H₂₃NO₂Si 0.2 EtOAc: C, 71.32; H, 6.75; N, 3.82.Found: C, 71.08; H, 6.64; N, 3.82.

EXAMPLE 746-(3-Ethynyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

A mixture of4,4-dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.7 g, 2 mmol) and potassium carbonate (2 g, excess) in anhydrousmethanol was stirred at rt under nitrogen for 4 hours. The mixture wastreated with ice-water (100 mL) and extracted with ethyl acetate (2×80mL). The organic layers were washed with brine and dried with MgSO₄. Thesolvent was removed and the title compound was obtained as a off-whitesolid (0.4 g, 72%): mp 171-172° C.; ¹H-NMR (DMSO-d₆) δ10.3, (s, 1H),7.78 (bs, 1H), 7.72-7.69 (m, 1H), 7.6-7.57 (m, 2H), 7.49-7.43 (m, 2H),6.97 (d, 1H, J=7.98 Hz), 4.25 (s, 1H), 1.67 (s, 6H); MS (EI) m/z277([M⁺], 100%); Anal. Calc. For C₁₈H₁₅NO₂.0.2 EtOAc: C, 76.56; H, 5.67;N, 4.75. Found: C, 76.34; H, 5.4; N, 4.7.

EXAMPLE 753-[3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-phenyl]-propynenitrile

To a stirred mixture of DMSO, acetonitrile and water (9 mL/3 mL/0.5 mL)was added at rt under nitrogen cuprous cyanide (0.193 g, 2.2 mmol),sodium iodide (11 mg, 0.072 mmol), and6-(3-ethynyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.2 g, 0.72 mmol). Chlorotrimethylsilane was then added to the abovemixture in a dropwise manner. After addition, the mixture was heated at50° C. for 72 hours. The reaction mixture was then cooled to rt andtreated with 0.5 N aqueous HCl cold solution (50 mL). The precipitateobtained was collected on a filter and washed with water. The solid waspurified on a silica gel column (hexane:ethyl acetate/2:1) to give thetitle compound as an off-white solid (10 mg, 4.6%): mp 212-213° C.;¹H-NMR (CHCl₃-d₆) δ7.96 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H, J=7.8 Hz),7.60 (d, 1H, J=7.69 Hz), 7.51 (d, 1H, J=7.77 Hz), 7.45 (dd, 1H, J=8.67,2.21 Hz), 7.31 (d, 1H, J=1.55 Hz), 6.91 (d, 1H, J=8.19 Hz), 1.8 (s, 6H);MS (EI) m/z 302 ([M⁺], 30%).

EXAMPLE 766-(3-Fluoro-5-nitro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-3-fluoro-5-nitrobenzene according to procedure B. A yellowsolid: mp 260-261° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.37 (bs, 1H),8.14-8.05 (m, 2H), 7.77-7.74 (m, 2H), 7.01 (d, 1H, J=7.94 Hz), 1.7 (s,6H); MS (ESI) m/z 315([M−H]⁺, 100%); Anal. Calc. For C₁₆H₁₃FN₂O₄: C,60.76; H, 4.14; N, 8.86. Found: C, 60.34; H, 4.2; N, 8.61.

EXAMPLE 776-(3-Chloro-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-3-chloro-5-fluorobenzene according to procedure B. A whitesolid: mp 193-194° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.67-7.64 (m,3H), 7.61-7.57 (m, 1H), 7.41-7.37 (m, 1H), 6.96 (d, 1H, J=8.72 Hz), 1.7(s, 6H); MS (APCI) m/z 306 ([M+H]⁺, 100%); Anal. Calc. For C₁₆H₁₃ClFNO₂:C, 62.86; H, 4.29; N, 4.58. Found: C, 62.98; H, 4.1; N, 4.6.

EXAMPLE 783-Chloro-5(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-3-chlorobenzonitrile according to procedure B. A white solid: mp256-257° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, H), 8.22 (bs, 1H), 8.15 (bs,1H), 7.98 (bs, 1H), 7.74-7.71 (m, 2H), 6.97 (d, 1H, J=8.09 Hz), 1.7 (s,6H); MS (ESI) m/z 311 ([M−H]⁻, 100%); Anal. Calc. For C₁₇H₁₃ClN₂O₂: C,65.29; H, 4.19; N, 8.96. Found: C, 65.25; H, 3.92; N, 8.71.

EXAMPLE 796-(3,5-Dinitro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-3,5-dinitrobenzene according to procedure B. A yellow solid: mp297-298° C.; ¹H-NMR (DMSO-d) δ10.4 (s, 1H), 8.88 (d, 2H, J=1.98 Hz),8.78 (bs, 1H), 7.78-7.82 (m, 2H), 7.04 (d, 1H, J=8.23 Hz), 1.7 (s, 6H);MS (APCI) m/z 343 ([M−H]⁻, 100%); Anal. Calc. For C₁₆H₁₃N₃O₆: C, 55.98;H, 3.82; N, 12.24. Found: C, 55.65; H, 3.7; N, 11.92.

EXAMPLE 805-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-isophthalonitrile

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and5-bromoisophthalonitrile according to procedure B. A white solid: mp288-289° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.58 (s, 2H), 8.40 (d, 1H,J=0.77 Hz), 7.80-7.75 (m, 2H), 6.99 (d, 1H, J=8.2 Hz), 1.7 (s, 6H); MS(EI) m/z 303 ([M⁺], 20%); Anal. Calc. For C₁₈H₁₃N₃O₂ 1.65 H₂O: C, 64.92;H, 4.93; N, 12.62 Found: C, 64.74; H, 4.69; N, 12.32.

EXAMPLE 814,4-Dimethyl-6-(3-thiazol-2-yl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A mixture of6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.25 g, 0.75 mmol), tri-n-butyl-thiazol-2-yl tin (0.5 g, 1.3 mmol) inDMF (5 mL) was degassed to remove oxygen and then heated under nitrogenat 90° C. for 3 hours. The reaction mixture was cooled to roomtemperature (rt) and treated with ice-water (70 mL). Ethyl acetate (100mL) was added and organic layer was separated, washed with brine, anddried (MgSO₄). After removal of solvent, the residue was purified by asilica gel column (hexane:ethyl acetate/1:1) to give the title compoundas a white solid (60 mg, 23%): mp 223-224° C.; ¹H-NMR (DMSO-d₆) δ10.4(s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 7.94 (bs, 1H), 7.67-7.61 (m, 4H),7.53 (t, 1H, J=7.68 Hz), 7.00 (d, 1H, J=8.81 Hz), 1.7 (s, 6H); MS (APCI)m/z 337 ([M+H]⁺, 100%); Anal. Calc. For C₁₉H₁₆N₂O₂S 0.25 H₂O: C, 66.94;H, 4.88; N, 8.22. Found: C, 66.57; H, 4.65; N, 7.92.

EXAMPLE 826-(3-Fluoro-5-methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and3-bromo-5-fluoroanisole according to procedure B. A white solid: mp181-182° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.62-7.59 (m, 2H),7.13-7.06 (m, 2H), 6.97-6.94 (d, 1H, J=8.89 Hz), 6.80 (dt, 1H, J=10.95,2.12 Hz), 3.8 (s, 3H), 1.7 (s, 6H); MS (ESI) m/z 302 ([M+H]⁺, 100%);Anal. Calc. For C₁₇H₁₆FNO₃ 0.1 H₂O: C, 67.36; H, 5.39; N, 4.62. Found:C, 67.11; H, 5.44; N, 4.48.

EXAMPLE 836-(3-Fluoro-5-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-3-fluoro-5-trifluoromethylbenzene according to procedure B. Awhite solid: mp 207-208° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.94-7.9(m, 2H), 7.73-7.7 (m, 2H), 7.63 (d, 1H, J=8.58 Hz), 6.99 (d, 1H, J=8.68Hz), 1.7 (s, 6H); MS (EI) m/z 339 ([M⁺], 60%); Anal. Calc. ForC₁₇H₁₃F₄NO₂: C, 60.18; H, 3.86; N, 4.13. Found: C, 59.9; H, 3.99; N,4.06.

EXAMPLE 846-(5-Bromo-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and3,5-dibromopyridine according to procedure B. A white solid: mp 211-212°C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.92 (d, 1H, J=1.9 Hz), 8.66 (d, 1H,J=2.09 Hz), 8.40 (t, H, J=2.02 Hz), 7.72-7.68 (m, 2H), 6.99 (d, 1H,J=8.1 Hz), 1.7 (s, 6H); MS (APCI) m/z 333 ([M+H]⁺, 100%), 335 ([M+H]⁺,100%); Anal. Calc. For C₁₅H ₁₃BrN₂O₂: C, 54.07; H, 3.93; N, 8.41. Found:C, 54.15; H, 3.89; N, 8.31.

EXAMPLE 856-(5-Bromo-1-oxy-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A mixture of6-(5-bromo-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.34 g, 1 mmol), hydrogen peroxide (30%, 5 mL) in acetic acid (5 mL)was heated at 60° C. for 3 hours. The reaction mixture was cooled to rtand neutralized by addition of a cold saturated sodium bicarbonatesolution. The white precipitate obtained was collected on a filter,washed with distilled water and dried to afford the title compound as awhite solid (0.35 g, 100%): mp 157-159° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s,1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.99 (s, 1H), 7.73-7.69 (m, 2H), 6.97(d, 1H, J=8.18 Hz), 1.7 (s, 6H); MS (APCI) m/z 349 ([M+H]⁺, 100%), 351([M+H]⁺, 100%); Anal. Calc. For C₁₅H₁₃BrN₂O₃2.5 H₂O: C, 45.70; H, 4.60;N, 7.11. Found: C, 45.34; H, 4.64; N, 7.

EXAMPLE 866-(3-Cyano-5-fluoro-phenyl)-4,4-dimethyl-2-oxo-4H-benzo[d][1,3]oxazine-1-carboxylicacid tert-butyl ester

A mixture of3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile(0.3 g,˜1 mmol), di-tert-butyl dicarbonate (0.33 g, 1.5 mmol), and DMAP(50 mg) in anhydrous acetonitrile was stirred at rt under nitrogen for 4minutes. The reaction mixture was washed with 1N aqueous HCl, brine,dried (MgSO₄). After removal of solvent, the title compound was obtainedas a white solid (0.25 g, 63%): mp 139-140° C.; ¹H-NMR (CDCl₃-d₆)δ7.66-7.63 (m, 2H), 7.53-7.48 (m, 2H), 7.38-7.35 (m, 2H), 1.79 (s, 6H),1.62 (s, 9H); MS (APCI) m/z 289 ([M−H]⁻100%); Anal. Calc. ForC₂₂H₂₁FN₂O₄: C, 66.66; H, 5.34; N, 7.07. Found: C, 66.7; H, 5.41; N, 7.

EXAMPLE 875-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile

Prepared from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-2-fluorobenzonitrile according to procedure B. A white solid: mp255-256° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.30 (dd, 1H, J=6.15, 2.41Hz), 8.12-8.07 (m, 1H), 7.76-7.58 (m, 3H), 6.97 (d, 1H, J=8.22 Hz), 1.7(s, 6H); MS (APCI) m/z 297 ([M+H]⁺, 100%); Anal. Calc. ForC₁₇H₁₃FN₂O₂0.1 H₂O: C, 68.50; H, 4.46; N, 9.40. Found: C, 68.27; H,4.81; N, 9.1.

EXAMPLE 884-(8-Fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile

8-Fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronicacid was prepared from6-bromo-8-Fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one usingthe procedure of example 4.

The title compound was prepared from8-fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronicacid and 4-bromo-2-cyanothiophene according to procedure B. A whitesolid: mp 250-251° C.; ¹H-NMR (DMSO-d₆) δ10.5 (s, 1H), 8.54 (d, 1H,J=1.42 Hz), 8.43 (d, 1H, J=1.35 Hz), 7.69 (dd, 1H, J=11.71, 1.54 Hz),7.58 (bs, 1H), 1.7 (s, 6H); MS (EI) m/z 302 ([M⁺], 50%); Anal. Calc. ForC₁₅H₁₁FN₂O₂S 0.45 H₂O: C, 58.04; H, 3.86; N, 9.02 Found: C, 58.4; H,3.89; N, 8.63.

EXAMPLE 893-Fluoro-5-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile

Prepared from8-fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronicacid and 5-bromo-3-fluorobenzonitrile according to procedure B. A whitesolid: mp 256-257° C.; ¹H-NMR (DMSO-d₆) δ10.5 (s, 1H), 8.20 (bs, 1H),8.06 (dt, 1H, J=10.48, 2.16 Hz), 7.85-7.82 (m, 1H), 7.77 (dd, 1H,J=11.89, 1.81 Hz), 7.63 (s, 1H), 1.7 (s, 6H); MS (EI) m/z 314 ([M⁺],60%).

EXAMPLE 905-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-3-carbonitrile

Prepared according to procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and2-bromo-4-thiophenecarbonitrile. An off-white solid: mp 255-260° C.;¹H-NMR (DMSO-d₆) δ10.36 (s, 1H), 8.48(d, 1H, J=1.1 Hz), 7.88-7.87 (d, 1HJ=1.3 Hz), 7.63 (d, 1H J=1.9 Hz),7.56-7.54 (dd, 1H, J=8.0, 2.0 Hz), 6.93(d, 1H, J=8.1 Hz), 1.64 (s, 6H). MS(−ESI) m/z 283 (M−H)⁻.

EXAMPLE 912-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-3-carbonitrile

Prepared according to procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and2-bromo-3-thiophenecarbonitrile. An off-white solid: mp 200-202° C.;¹H-NMR (DMSO-d₆) δ10.49 (s, 1H), 7.75 (m, 1H), 7.63 (d, 1H, J=2.2 Hz),7.59 (m, 1H), 7.50 (m, 1H), 7.02 (d, 1H, J=8.1 Hz), 1.63 (s, 6H);MS(−ESI) m/z 283 (M−H)⁻.

EXAMPLE 926-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

A mixture of 5-[3-bromo-phenyl]-[1,3,4]oxathiazole-2-one (21.25 g, 82.3mmol), ethylcyano formate (32.5 mL, 329 mmol) in o-xylene (500 mL) washeated to 150° C. for 60 hours. After the solvent was removed from thereaction mixture, the product was recrystallized from ethanol to give3-[3-bromo-phenyl]-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester aswhite crystals (17.5 g, 68%): mp 87-90° C.; ¹H-NMR (CDCl₃) δ8.53 (t, 1H,J=1.76 Hz), 8.28 (dt, 1H, J=5.4, 1.2 Hz), 7.62 (dq, 1H, J=5.1, 1.0 Hz),7.36 (t, 1H, J=7.9 Hz), 4.55 (q, 2H, J=7.1 Hz), 1.48 (t, 3H, J=7.1 Hz);MS ((+)APCI) [M+H]⁺ @ m/z 313/315. Anal. Calc. For C₁₁H₉BrN₂O₂S: C,42.19; H, 2.90; N, 8.94. Found: C, 41.81; H, 3.08; N, 8.78.

A mixture of 3-[3-bromo-phenyl]-[1,2,4]thiadiazole-5-carboxylic acidethyl ester (16.8 g, 53.5 mmol), sodium hydroxide (2.4 g, 58.8 mmol),distilled water (120 mL), and ethanol (20 mL) was heated to 100° C. for2 hours. The reaction mixture was cooled to room temperature.Concentrated hydrochloric acid (5.1 mL) was added, and the reactionmixture re-heated to 100° C. for 3 hours. The solution was cooled toroom temperature and extracted with diethyl ether (3×150 mL). Thecombined organic layers were washed with distilled water (3×100 mL), anddried over MgSO₄. After the solvent was removed,3-[3-bromo-phenyl]-[1,2,4]thiadiazole was obtained as white needles(12.7 g, 99%): mp 69-71° C.; ¹H-NMR (CDCl₃) δ9.89 (s, 1H), 8.52 (t, 1H,J=1.8 Hz), 8.28 (dt, 1H, J=5.2, 1.3 Hz), 7.61 (dq, 1H, J=4.9, 1.1 Hz),7.35 (t, 1H, J=7.9 Hz); MS ((+)APCI) [M+H]⁺ @ m/z 241/243. Anal. Calc.For C₈H₅BrN₂S: C, 39.85; H, 2.09; N, 11.62. Found: C, 39.82; H, 2.43; N,11.33.

According to procedure B,(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid wascoupled with 3-[3-bromo-phenyl]-[1,2,4]thiadiazole to yield6-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-oneas an off-white solid (0.5 g, 35%): mp 214-216° C.; ¹H-NMR (DMSO-d₆)δ10.40 (s, 1H), 10.36 (s, 1H), 8.49 (s, 1H), 8.23 (d, 1H, J=7.7 Hz),7.83 (d, 1H, J=7.9 Hz), 7.66-7.61 (m, 3H), 7.02 (t, 1H, J=4.4 Hz), 1.70(s, 6H); MS ((+)APCI) [M+H]⁺ @ m/z 338.

EXAMPLE 936-(3-Fluoro-5-thiophen-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared from6-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-oneand 3-thiophene boronic acid according to procedure B. A brownish-orangesolid: mp 200-203° C.; ¹H-NMR (CDCl₃) δ8.62 (s, 1H), 7.53 (q, 1H, J=1.4Hz), 7.50 (d, 1H, J=1.5 Hz), 7.49 (d, 1H, J=2.0 Hz), 7.45-7.40 (m, 1H),7.35 (d, 1H, J=1.8 Hz), 7.27-7.24 (m, 2H), 7.15 (dt, 1H, J=5.8, 2.0 Hz),694 (d, 1H, J=8.2 Hz), 1.80 (s, 6H); MS ((−)APCI) [M−H]⁻ @ m/z 352.Anal. Calc. For C₂₀H₁₆FNO₂S 0.50 H₂O: C, 66.28; H, 4.73; N, 3.87. Found:C, 66.54; H, 5.03; N, 3.52.

EXAMPLE 942-(4,4-Dimethyl-2-oxo-1,4dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1-carboxylicacid tert-butyl ester

A solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.87 g, 3.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (96 mg,0.08 mmol) in toluene (40 mL) was stirred under a flow of nitrogen for25 min. To the solution was added sequentially1-t-butoxycarbonylpyrrole-2-boronic acid (1.4 g, 7.0 mmol) in absoluteethanol (10 mL) and potassium carbonate (0.94 g, 7.0 mmol) in water (10mL). The mixture was heated at 80° C. for 16 h and allowed to cool tort. The reaction mixture was poured into aqueous saturated sodiumbicarbonate solution (100 mL) and extracted with ethyl acetate (3×100mL). The organic layers were combined, washed with water (100 mL) andbrine (50 mL) and dried over magnesium sulfate. The solution wasfiltered, concentrated in vacuo, and the residue was purified by flashcolumn chromatography on silica gel (30% ethyl acetate/hexane) to givethe title compound as an off-white powder (0.7 g, 62%): mp 176° C. ¹HNMR (CDCl₃) δ1.40 (s, 9H), 1.73 (s, 6H), 6.17 (dd, 1H, J=1.8, 3.3 Hz),6.22 (dd, 1H, J=3.3, 3.3 Hz), 6.77 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=1.8Hz), 7.23 (dd, 1H, J=1.8, 8.1 Hz), 7.33 (dd, 1H, J=1.8, 3.3 Hz), 7.69(bs, 1H). MS ((−) ESI) m/z 341 [M−H]⁻. Anal. Calcd for C₁₉H₂₂N₂O₄: C,66.65; H, 6.48; N, 8.18. Found: C, 65.46; H, 6.51; N, 7.74.

EXAMPLE 952-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-nitro-pyrrole-1-carboxylicacid tert-butyl ester

To a solution of 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester (0.7 g,2.0 mmol) in acetonitrile (25 mL) and dichloromethane (1 mL) at roomtemperature was added silver nitrate (0.37 g, 2.1 mmol). After 5 min,acetyl chloride (0.15 mL, 2.0 mmol) in acetonitrile (3 mL) was added andthe solution was allowed to stir for 2 h. The reaction mixture waspoured into water (50 mL) and extracted with ethyl ether (2×50 mL). Theorganic layers were combined, washed with brine (30 mL) and dried overmagnesium sulfate. The solution was filtered, concentrated in vacuo andthe residue was purified by flash column chromatography on silica gel(30% ethyl acetate/hexane) to give a yellow oil which crystallized from5% ethyl acetate/hexane to give the title compound as a bright yellowpowder (350 mg, 45%): mp 125° C. ¹H NMR (CDCl₃) δ1.47 (s, 9H, 1.75 (s,6H), 6.26 (d, 1H, J=4.2 Hz), 6.87 (d, 1H, J=8.1 Hz), 7.19 (d, 1H, J=4.2Hz), 7.34 (d, 1H, J=2 Hz), 7.4 (dd, 1H, J=1.8, 8.1 Hz), 8.17 (bs, 1H).MS ((+) APCI) m/z 388 [M+H]⁺. Anal. Calcd for C₁₉H₂₁N₃O₆: C, 58.91; H,5.46; N, 10.85. Found: C, 58.4; H, 5.55; N, 10.18.

EXAMPLE 964,4-Dimethyl-6-(5-nitro-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one

2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-nitro-pyrrole-1-carboxylicacid tert-butyl ester (0.7 g, 1.8 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 180°C. After 10 min at this temperature, the flask was removed from the oilbath and allowed to cool to rt. The brown residue was washed into alarger flask with dichloromethane/ethyl acetate and adsorbed onto asmall amount of silica gel. Purification by flash column chromatographyon silica gel (60% ethyl acetate/hexane) gave the title compound as abrown powder (200 mg, 40%): mp 265° C. (dec). ¹H NMR (DMSO-d₆) δ1.65 (s,6H), 6.81 (d, 1H, J=4.4 Hz), 6.90 (d, 1H, J=8.6 Hz), 7.25 (d, 1H, J=4.2Hz), 7.79 (dd, 1H, J=2, 8.3 Hz), 7.91 (d, 1H, J=2 Hz), 10.37 (s, 1H),13.17 (bs, 1H), MS ((−) ESI) m/z 286 [M−H]⁻. Anal. Calcd for C₁₄H₁₃N₃O₄:C, 58.53; H, 4.56; N, 14.63. Found: C, 58.25; H, 5.10; N, 12.57.

EXAMPLE 974,4-Dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole1-carboxylic acid tert-butyl ester (3.5 g, 10 mmol) was placed in a 25mL round bottomed flask stoppered with a rubber septum and equipped withnitrogen inlet and a needle to allow gaseous outflow. A vigorous flow ofnitrogen was maintained as the flask was placed in an oil bath andheated to 180° C. After 10 min at this temperature, the flask wasremoved from the oil bath and allowed to cool. The brown residue waswashed into a larger flask with dichloromethane/ethyl acetate andadsorbed onto a small amount of silica gel. Purification by flash columnchromatography on silica gel (60% ethyl acetate/hexane) gave the titlecompound as a green solid (2 g, 80%): mp 202° C. (dec). ¹H NMR (CDCl₃)δ1.75 (s, 6H), 6.30 (m, 1H), 6.45 (m, 1H), 6.85 (d, 1H, J=8.5 Hz), 6.86(m, 1H), 7.24 (d, 1H, J=2 Hz), 7.33 (dd, 1H, J=2, 8.4 Hz), 8.44 (bs,1H), 8.66 (s, 1H). MS ((+) APCI) m/z 243 [M+H]⁺. Anal. Calcd forC₁₄H₁₄N₂O₂: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.20; H, 5.96; N,11.29.

EXAMPLE 984,4-Dimethyl-6-(1-methyl-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a mixture of4,4-dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one(1.5 g, 6.2 mmol) in dimethylformamide (20 mL) at room temperature wasadded sequentially potassium carbonate (4.28 g, 31 mmol) and a solutionof methyl iodide (1.16 mL, 19 mmol) in dimethylformamide (5 mL). After 1h, the reaction mixture was boiled. The reaction was cooled to roomtemperature, poured into water (50 mL) and extracted with ethyl ether(2×50 mL). The organic layers were combined, washed with brine (30 mL),dried over magnesium sulfate, filtered and concentrated in vacuo.Purification by flash column chromatography on silica gel (40% ethylacetate/hexane) gave the title compound as an off-white powder (0.5 g,31%) mp 230° C. ¹H NMR (CDCl₃) δ1.71 (s, 6H), 3.42 (s, 3H), 6.31 (dd,1H, J=2.9, 5.9 Hz), 6.47 (m, 1H), 6.88 (m, 1H), 6.94 (d, 1H, J=8.6 Hz),7.26 (d, 1H, J=2.2 Hz), 7.41 (dd, 1H, J=2.2, 8.6 Hz), 8.43 (bs, 1H). MS((−) ESI) m/z 255 [M−H]⁻. Anal. Calcd for C₁₅H₁₆N₂O₂: C, 70.29; H, 6.29;N, 10.93. Found: C, 68.59; H, 6.16; N, 10.49.

EXAMPLE 994,4-Dimethyl-6-(1-methyl-5-nitro-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a solution of4,4-dimethyl-6-(1-methyl-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one(0.3 g, 1.2 mmol) in acetonitrile (20 mL) was added silver nitrate (0.21g, 1.26 mmol). The solution was cooled to −78° C. and treated with asolution of acetyl chloride (0.08 mL, 1.2 mmol) in acetonitrile (1 mL).The reaction mixture was allowed to warm to room temperature. After 1 h,the reaction mixture was poured into water (50 mL) and extracted withethyl ether (2×50 mL). The organic layers were combined, washed withbrine (30 mL), dried over magnesium sulfate, filtered and concentratedin vacuo. Purification by flash column chromatography on silica gel (40%ethyl acetate/hexane) gave the title compound (5 mg, 1%) as a yellowsolid, mp 180-185° C. ¹H NMR (CDCl₃) δ1.75 (s, 6H), 3.45 (s, 3H), 6.57(dd, 1H, J=2.9, 4.3 Hz), 7.04 (d, 1H, J=8.5 Hz), 7.22 (dd, 1H, J=2.5,4.3 Hz), 7.36 (d, 1H, J=2.1 Hz), 7.56 (dd, 1H, J=2.1, 8.5 Hz), 9.67 (bs,1H. MS ((+) APCI) m/z 302 [M+H]⁺.

EXAMPLE 100 5-Bromo-4-ethylthiophene-2-carboxaldehyde

Prepared from 2-bromo-3-ethylthiophene in a similar manner to theexample 19. ¹H-NMR(DMSO-d₆) δ9.82 (s, 1H), 7.81 (s, 1H), 2.5 (q, 2H,J=7.4 Hz), 1.15 (t, 3H, J=7.5 Hz).

EXAMPLE 101 5-Bromo-4-ethylthiophene-2 carbonitrile

Prepared from 5-bromo-4-ethylthiophene-2-carboxaldehyde using thesimilar procedure of example 18. IR(KBr) 2221 cm⁻¹; ¹H-NMR (DMSO-d₆)δ7.87 (s, 1H), 2.55 (q, 2H, J=7.3 Hz), 1.18 (t, 3H, J=7.6 Hz). MS (EI)m/z 215/217(M⁺).

EXAMPLE 102 5Bromo-4-n-propylthiophene-2-carboxaldehyde

Prepared from 2-bromo-3-n-propylthiophene in a similar manner to theexample 19. ¹H-NMR(DMSO-d₆) δ9.82 (s, 1H), 2.6-2.5 (m, 2H), 1.65-1.51(m, 2H), 1.0 (t, 3H, J=4.7 Hz).

EXAMPLE 103 5-Bromo-4-n-propylthiophenecarbonitrile

Prepared from 5-bromo-4-n-propylthiophene-2-carboxaldehyde using thesimilar procedure of example 18. ¹H-NMR(DMSO-d₆) δ7.87 (s, 1H), 2.5 (t,2H, J=5.2 Hz), 1.64-1.5 (m, 2H), 1.91 (t, 3H, J=5.1 Hz). MS(EI) m/z229-231(M⁺).

EXAMPLE 104 5-Bromo-4-n-butylthiophenecarboxaldehyde

Prepared from 2-bromo-3-n-butylthiophene in a similar manner to theexample 19. IR(KBr) 1660 cm⁻¹. ¹H-NMR (DMSO-d₆) δ9.78 (s, 1H), 7.85 (s,1H), 2.57-2.53 (m, 2H), 1.57-1.53 (m, 2H), 1.32-1.25 (m, 2H), 0.88 (t,3H, J=5.2 Hz). MS (EI) m/z 246(M⁺).

EXAMPLE 105 5-Bromo-4-n-butylthiophenecarbonitrile

Prepared from 5-bromo-4-n-butylthiophenecarboxaldehyde using the similarprocedure of example 18. ¹H-NMR(DMSO-d₆) δ7.87 (s, 1H), 2.58-2.44 (m,2H), 1.65-1.48 (m, 2H), 1.38-1.23 (m, 2H), 0.89 (t, 3H, J=5.3 Hz). MS(EI) m/z 243 (M⁺).

EXAMPLE 1063-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-benzonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromobenzonitrile. Tan powder: mp 245-247° C.¹H-NMR(DMSO-d₆) δ10.31 (s, 1H), 8.21 (s, 1H), 8.02 (d, 1H, J=8.0 Hz),7.78 (d, 1H, J=7.7 Hz), 7.68-7.61 (n, 3H), 6.97 (d, 1H, J=8.2 Hz),1.98-1.96 (m, 4H), 1.75-1.64 (m, 5H), 1.40-1.32 (m, 1H). MS (EI) m/z 318[M⁺]. Anal. Calc. For C₂₀H₁₈N₂O₂.1/2 H₂O: C 73.38; H, 5.85; N, 8.56.Found: C, 73.86; H, 5.81; N, 8.22.

EXAMPLE 1073-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-5-fluorobenzonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronicacid and 3-bromo-5-fluorobenzonitrile. White powder: mp 250-253° C. IR(KBr) 2220 cm⁻¹. ¹H-NMR (DMSO-d₆) δ10.34 (s, 1H), 8.13 (s, 1H), 8.0 (d,1H, J=10.6 Hz), 7.80-7.7 (m, 3H, 6.98-6.95 (d, 1H, J=8.1 Hz), 1.99-1.97(m, 4H), 1.76-1.65 (m, 6H), 1.37-1.33 (m, 1H). MS (EI) m/z 336 (M⁺). ACalc. For C₂₀H₁₇FN₂O₂H₂O: C, 67.78; H, 5.40; N, 7.90. Found: C, 67.9; H,4.93; N, 7.67.

EXAMPLE 1084-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-2-thiophenecarbonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromo-5-cyanothiophene. White crystals: mp 230-232°C. IR (KBr) 2200 cm⁻¹. ¹H-NMR (DMSO-d₆) δ10.29 (s, 1H), 8.49 (s, 1H),8.33 (s, 1H), 7.69-7.63 (m, 2H), 6.93-6.91 (d, 1H, J=8.2 Hz), 199-187(m, 4H), 1.73-1.64 (m, 5H), 1.38-1.31 (m, 1H). MS(+)APCI m/z 325 (M+H)⁺.Anal. Calc. For C₁₈H₁₆N₂O₂S1/4H₂O: C, 65.73; H, 5.06; N, 8.52. Found: C,65.55; H, 506; N, 8.22.

EXAMPLE 1095-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-2-thiophenecarbonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 2-bromo-5-cyanothiophene Tan powder: mp 243-245° C.¹H-NMR(DMSO-d₆) δ10.41(s, 1H), 7.98-7.97 (d, 1H, J=3.9 Hz), 7.67-7.60(m, 3H), 6.97-6.94 (d, 1H, J=8.3 Hz), 1.98-1.92 (m, 4H), 174-164 (m,5H), 1.45-1.21 (m, 1H). MS (EI) m/z 324 (M⁺). Anal. Calc. ForC₁₈H₁₆N₂O₂S 1/2 H₂O: C, 65.08; H, 5.04; N, 8.18. Found: C, 64.84; H,5.09; N, 8.40.

EXAMPLE 1105-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-4-methyl-2-thiophenecarbonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 2-bromo-3-methyl-5-cyanothiophene. White powder: mp200-203° C. ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 7.85 (s, 1H), 7.43-7.40 (m,2H), 7.0 (d, 1H, J=8.8 Hz), 2.27 (s,3H), 2.00-1.62 (m, 9H), 1.42-123 (m,1H). MS(EI) m/z 338 (M⁺). Anal. Calc. For C₁₉H₁₈N₂O₂S: C, 67.43; H,5.36; N, 8.28. Found: C, 67.12; H, 5.45; N, 8.05.

EXAMPLE 1115-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-ethyl-thiophene-2-carbonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 2-bromo-3-ethyl-5-cyanothiophene. White crystals: mp160-162° C. ¹H-NMR(DMSO-d₆) δ10.46 (s, 1H), 7.96 (s, 1H), 7.40-7.38 (m,2H), 7.02-6.99 (d, 1H, J=8.8 Hz), 2.61 (q, 2H, J=7.5 Hz), 164 (s, 6H),1.16 (t, 3H, J=7.6 Hz). MS (+) APCI m/z [M+H⁺ 313. Anal. Calc. ForC₁₇H₁₆N₂O₂S.1/4 H₂O: C, 64.43; H, 5.25; N, 8.84. Found: C, 64.77; H,5.23; N, 8.68.

EXAMPLE 1125-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-n-proyl-thiophene-2-carbonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 2-bromo-3-n-propyl-5-thiophenecarbonitrile. Whitecrystals: mp 160-162° C. IR (KBr) 2220 cm⁻¹. ¹H-NMR(DMSO-d₆) δ10.47 (s,1H), 7.93 (s, 1H), 7.38-7.36 (m, 2H), 7.01 (d, 1H, J=8.7 Hz), 2.59-2.48(m, 2H), 1.64-1.51 (m, 2H), 0.85 (t, 3H, J=7.3 Hz). MS(−-ESI) m/z [M−H]⁻325. Anal. Calc. For C₁₈H₁₈N₂O₂S.3/4 H₂O: C, 63.60; H, 5.78; N, 8.24. C,63.48; H, 5.59; N, 8.04.

EXAMPLE 1135-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-n-butyl-thiophene-2-carbonitrile

Prepared according to Procedure B fromspiro-(4,1′-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 2-bromo-3-n-butyl-5-thiophenecarbonitrile. Whitecrystals: mp 167-168° C. ¹H-NMR(DMSO-d₆) δ10.46 (s, 1H), 7.93 (s, 1H),7.38-7.36 (m, 2H), 7.01 (d, 1H, J=8.7 Hz), 2.59 (t, 2H, J=8.1 Hz), 1.63(s, 6H), 1.58-1.51 (m, 2H), 1.48-1.17 (m, 2H), 0.82 (t, 3H, J=7.4 Hz),MS(−ESI) m/z [M−H]⁻ 339. Anal. Calc. For C₁₉H₂₀N₂O₂S.1/4 H₂O: C, 66.16;H, 5.99; N, 8.12. Found: C, 66.33; H, 5.92; N, 7.85.

EXAMPLE 1146-(4-Cyano-3-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d]1,3]-oxazin-2-one

A solution of 4-cyano-3-fluoro-bromobenzene (0.6 g, 3.0 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 mL) was stirred under N₂ for 20 minutes. To thismixture was then added(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.0g, 4.5 mmol) and sodium carbonate (1.1 g, 10.6 mmol) in water (5 mL).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (3×50 mL). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc:hexane=1:2) to afford the title compound (0.05 g, 6%) as anoff-white solid. mp: 272-275° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s, 1H), 8.0(t, 1H, J=7.7 Hz), 7.9 (dd, 1H, J=10.3,1.3 Hz), 7.8 (dd, 1H, J=6.8, 1.4Hz), 7.7 (m, 2H), 6.9 (d, 1H, J=8.9 Hz), 1.7 (s, 6H); MS (EI) M⁺ @ m/z296.

EXAMPLE 1156-(4-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

Prepared according to Procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-4-fluorobenzene. Off-white crystals: mp 232-233° C.¹H-NMR(DMSO-d₆) δ10.3 (s, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.28 (m, 2H),6.96 (d, 1H, J=8.9 Hz), 1.63 (s, 6H).

EXAMPLE 1166-(3,4-Difluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared according to Procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-3, 4-difluorobenzene. Off-white crystals: mp 207-208° C.¹H-NMR(DMSO-d₆) δ10.35 (s, 1H), 7.79 (m, 1H), 7.40-7.63 (m, 4H), 6.95(d, 1H, J=8.9 Hz), 1.62 (s, 6H).

EXAMPLE 1176-(2-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one

Prepared according to Procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and1-bromo-2-fluorobenzene. Off-white crystals: mp 164-165° C.¹H-NMR(DMSO-d₆) δ10.33 (s, 1H), 7.56 (n, 1H), 7.25-7.45 (m, 4H) 6.98 (d,1H, J=8.7 Hz), 1.64 (s, 6H).

EXAMPLE 1183-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)phenylacetonitrile

Prepared from 3-bromophenylacetonitrile and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-oxazin-6-yl)boronic acid. Whitesolid: mp 188-190° C.; ¹H-NMR (DMSO-d₆) δ10.33 (s, 1H), 7.62 (m, 2H),7.55 (m, 2H), 7.48 (d, 1H, J=8.00 Hz), 7.33 (d, 1H, J=7.57 Hz), 6.99 (d,1H, J=8.81 Hz), 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291(M−H). Anal. Calc.For C₁₈H₁₆N₂O₂.0.3 H₂O: C, 72.61; H, 5.62; N, 9.41. Found: C, 73.00; H,5.43; N, 8.81

EXAMPLE 1195-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile

The title compound was prepared according to the procedure B from2-bromo-5-cyanofuran (1.0 g, 5.6 mmol) (J. Med. Chem. (1997), 40(23),3804-3819) and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.8g, 8.18 mmol) as a white solid (0.39 g, 1.45 mmol, 17%): mp. 257-260°C.; ¹H-NMR (DMSO-d₆) δ10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1H,J=3.8 Hz), 6.98 (d, 1H, J=8.9 Hz), 1.66 (s, 6H); MS ((+)-APCI) m/z=269(M+H)⁺.

EXAMPLE 1203-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile

A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in drymethanol (5 mL) under nitrogen was treated with trimethylorthoformate(0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), andthen heated under reflux. After 16 h, the mixture was evaporated and theresidue partitioned between water and Et₂O. the organic layer was washedwith sat. sodium hydrogen carbonate solution, water, brine, dried(MgSO₄) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g,0.84 mmol, 84%): ¹H-NMR (CDCl₃) δ7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H),7.10 (dt, 1H, J=8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M⁺).

A solution of the last cited compound (3.077 g, 13.2 mmol) in drytoluene (80 mL) at −78° C. under nitrogen was treated with adi-iso-butylaluminum hydride in toluene (1M, 15.7 mL, 15.7 mmol). After1 h at −78° C., the mixture was quenched with aqueous HCl (3M, 16 mL).The mixture was warmed to RT, partitioned between EtOAc/H₂O, the aqueouslayer was re-extracted with EtOAc, and the combined organic layers werewashed with water, dried (MgSO₄) and evaporated to afford3-bromo-2-fluorobenzaldehyde (2.63 g, 12.9 mmol, 98%), which was usedwithout further purification: ¹H-NMR (CDCl₃) δ10.35 (s, 1H), 7.82 (r,2H), 7.18 (t, 7.8 Hz).

A mixture of the last cited compound (2.63 g, 12.9 mmol), hydroxylaminehydrochloride (1.0 g, 14 mmol) and potassium acetate (1.37 g, 14 mmol)was placed in ethanol/H₂O (60 mL, 8:2) and the mixture was heated underreflux. After 30 min. the mixture was cooled, evaporated and partitionedbetween EtOAc and water. The organic layer was washed with brine, dried(MgSO₄) and evaporated to give 3-bromo-2-fluorobenzaldoxime which wasused without further characterization.

A solution of the last cited compound (0.75 g, 3.43 mmol) andtetrakis(triphenylphosphine) palladium(0) (0.2 g) were stirred indimethoxy ethane (30 mL) at room temperature under nitrogen. After 15min., (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronicacid (1.1 g, 5.0 mmol) and sodium carbonate (1.35 g) in water (10 mL)were added and the mixture heated under reflux. After 16 h., the mixturewas cooled, partitioned between water and EtOAc, the organic layer waswashed with sat. sodium carbonate solution, brine, dried (MgSO₄) andevaporated. The residue was then dissolved in acetonitrile (50 mL),treated with copper acetate (0.2 g) and heated under reflux. After 16 h,the mixture was cooled and evaporated. The residue was partitionedbetween water and EtOAc, the organic layer was then washed with dilutesulfuric acid (1N), water, brine, dried (MgSO₄) and evaporated. Theresidue was then subjected to column chromatography (SiO₂, EtOAc/hexane,gradient elution), and then crystallized from EtOAc-hexane to afford thetitle compound (0.176 g, 0.59 mmol, 17%) as a white solid: mp. 192-198°C.; ¹H-NMR (CDCl₃) δ9.15 (s, 1H), 7.69-7.58 (m, 2H), 7.42-7.31 (m, 3H),6.99 (d, 1H, J=8.2 Hz), 1.78 (s, 6H); MS ((+)ESI) 297 [M+H]⁺.

EXAMPLE 121 Pharmacology

The compounds of this invention were tested in the relevant assay asdescribed below and their potency are in the range of 0.01 nM to 5 μM inthe in vitro assays and 0.001 to 300 mg/kg in the in vivo assays.

TABLE 1 Potency of the selected cyclocarbamate derivatives as PRantagonists in some in vitro and in vivo models:

hPR Decidualization CV-1 Compound R₁ R₂ R₃ IC₅₀ (nM) IC₅₀ (mg/kg) 13-cyano-4- Me Me 55 80% @ 1** fluorophenyl 2 3-fluoro-5- Me Me 54 50% @1 trifluormethyl- phenyl 3 3-fluorophenyl Me Me 6 80% @ 3 43,5-dichloro- Me Me 134 60% @ 1 phenyl 5 5-cyano-2- Me Me 68 60% @ 1fluorophenyl 6 3-fluoro-5- Me Me 11.5 50% @ 1 nitrophenyl 7 7-(2-cyano-Me Me 30 75% @ 3 furyl) 8 3-bromo-5- Me Me 11 50% @ 3 fluorophenyl 93-cyano-4- Me Me 13 6.96 ± 0.84 fluorophenyl 10 5-(2-cyano-4-spirocyclohexyl 2.7 50% @ 10 methylthiophenyl 11 5-(2-cyanothio-spirocyclohexyl 12 50% @ 10 phenyl) 12 5-(2-cyanothio- Me Me 19 3.34 ±0.22 phenyl) 13 3-bromophenyl Me Me 11.5 3 14 3-chloro-5-fluoro- Me Me22 50% @ 3 phenyl 15 3-cyano-5-fluoro- cyclopropyl cyclopropyl 22 3phenyl 16 5-(3-bromo- Me Me 26 50% @ 3 pyridyl) 17 4-(2-cyanothio- Me Me12.7 2.3 ± 0.46 phenyl) 18 5-(2-cyano-4- Me Me 5.23 1.5methylthiophenyl) 19 3-cyano-5-fluoro- Me Me 13.8 0.35 phenyl 203-chloro-4-fluoro- Me Me 37 1 phenyl ND, not determined; **Percentageinhibition at the dose specified

A. In-vitro Biology

The in-vitro biology is determined by (1) competitive RadioligandBinding: using the A-form of the human progesterone receptor withprogesterone as the radioligand; (2) co-transfection assay, whichprovides functional activity expressed as agonist EC50 and AntagonistIC50 values; (3) a T47D cell proliferation, which is a furtherfunctional assay which also provides agonist and antagonist data; and(4) T47D cell alkaline phosphatase assay, which is a further functionalassay which also provides agonist and antagonist data.

1. hPR Binding Assay

This assay is carried out in accordance with: Pathirana, C.; Stein, R.B.; Berger, T. S.; Fenical, W.; Ianiro, T.; Mais, D. E.; Torres, A.;Glodman, M. E., Nonsteroidal human progesterone receptor modulators fromthe marine alga cymoplia barbata, J. Steroid Biochem. Mol. Biol., 1992,41, 733-738.

2. PRE-luciferase assay in CV-1 Cells

The object of this assay is to determine a compound's progestational orantiprogestational potency based on its effect on PRE-luciferasereporter activity in CV-1 cells co-transfected with human PR andPRE-luciferase plasmids. The materials methods used in the assay are asfollows.

a. Medium

The growth medium was as follows:

DMEM (BioWhittaker) containing 10% (v/v) fetal bovine serum (heatinactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml penicillin,100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL). The experimentalmedium was as follows: DMEM (BioWhittaker), phenol red-free, containing10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0.1mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/mlstreptonycin, and 2 mM GlutaMax (GIBCO, BRL).

b. Cell Culture, Transfection, Treatment, and Luciferase assay

Stock CV-1 cells are maintained in growth medium Co-transfection is doneusing 1.2×10⁷ cells, 5 mg pLEM plasmid with hPR-B inserted at Sph1 andBamH1 sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferasesequence, and 50 mg sonicated calf thymus DNA as carrier DNA in 250 ml.Electroporation is carried out at 260 V and 1,000 mF in a Biorad GenePulser II. After electroporation, cells are resuspended in growth mediumand plated in 96-well plate at 40,000 cells/well in 200 μl. Followingovernight incubation, the medium is changed to experimental medium.Cells are then treated with reference or test compounds in experimentalmedium. Compounds are tested for antiprogestational activity in thepresence of 3 nM progesterone. Twenty-four hr. after treatment, themedium is discarded, cells are washed three times with D-PBS (GIBCO,BRL). Fifty μl of cell lysis buffer (Promega, Madison, Wis.) is added toeach well and the plates are shaken for 15 min in a Titer Plate Shaker(Lab Line Instrument, Inc.). Luciferase activity is measured usingluciferase reagents from Promega.

c. Analysis of Results

Each treatment consists of at least 4 replicates. Log transformed dataare used for analysis of variance and nonlinear dose response curvefitting for both agonist and antagonist modes. Huber weighting is usedto downweight the effects of outliers. EC₅₀ or IC₅₀ values arecalculated from the retransformed values. JMP software (SAS Institute,Inc.) is used for both one-way analysis of variance and non-linearresponse analyses.

d. Reference Compounds

Progesterone and trimegestone are reference progestins and RU486 is thereference antiprogestin. All reference compounds are run in fulldose-response curves and the EC₅₀ or IC₅₀ values are calculated.

TABLE 2 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three individual studiesEC50 95% CI Compound Exp. (nM) SE lower upper Progesterone 1 0.616 0.0260.509 0.746 2 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.00943 0.0067 0.0003 0.0055 0.0082

TABLE 3 Estimated IC₅₀, standard error (SE), and 95% confident interval(CI) for the antiprogestin, RU486 from three individual studies IC 5095% CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.019 0.0422 0.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027

Progestational activity: Compounds that increase PRE-luciferase activitysignificantly (p<0.05) compared to vehicle control are consideredactive.

Antiprogestational activity: Compounds that decrease 3 nM progesteroneinduced PRE-luciferase activity significantly (p<0.05)

EC₅₀: Concentration of a compound that gives half-maximal increasePRE-luciferase activity (default-nM) with SE.

IC₅₀: Concentration of a compound that gives half-maximal decrease in 3nM progesterone induced PRE-luciferase activity (default-nM) with SE.

3. T47D Cell Proliferation Assay

The objective of this assay is the determination of progestational andantiprogestational potency by using a cell proliferation assay in T47Dcells. A compound's effect on DNA synthesis in T47D cells is measured.The materials and methods used in this assay are as follows.

a. Growth Medium

DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovineserum (not heat-inactivated), 100 U/ml penicillin, 100 mg/mlstreptomycin, and 2 mM GlutaMax (GIBCO, BRL).

b. Treatment Medium

Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol red-freesupplemented with 0.5% charcoal stripped fetal bovine serum, 100 U/mlpenicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).

c. Cell Culture

Stock T47 D cells are maintained in growth medium. For BrdUincorporation assay, cells are plated in 96-well plates (Falcon, BectonDickinson Labware) at 10,000 cells/well in growth medium After overnightincubation, the medium is changed to treatment medium and cells arecultured for an additional 24 hr before treatment. Stock compounds aredissolved in appropriate vehicle (100% ethanol or 50% ethanol/50% DMSO),subsequently diluted in treatment medium and added to the cells.Progestin and antiprogestin reference compounds are run in fulldose-response curves. The final concentration of vehicle is 0.1%. Incontrol wells, cells receive vehicle only. Antiprogestins are tested inthe presence of 0.03 nM trimegestone, the reference progestin agonist.Twenty-four hours after treatment, the medium is discarded and cells arelabeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, Ill.)in treatment medium for 4 hr.

d. Cell Proliferation Assay

At the end of BrdU labeling, the medium is removed and BrdUincorporation is measured using a cell proliferation ELISA kit (#RPN250, Amersham Life Science) according to manufacturer's instructions.Briefly, cells are fixed in an ethanol containing fixative for 30 min,followed by incubation in a blocking buffer for 30 min to reducebackground. Peroxidase-labeled anti-BrdU antibody is added to the wellsand incubated for 60 min. The cells are rinsed three times with PBS andincubated with 3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10-20min depending upon the potency of tested compounds. Then 25 μl of 1 Msulfuric acid is added to each well to stop color reaction and opticaldensity is read in a plate reader at 450 nm within 5 min.

e. Analysis of Results

Square root-transformed data are used for analysis of variance andnonlinear dose response curve fitting for both agonist and antagonistmodes. Huber weighting is used to downweight the effects of outliers.EC₅₀ or IC₅₀ values are calculated from the retransformed values. JMPsoftware (SAS Institute, Inc.) is used for both one-way analysis ofvariance and non-linear dose response analyses in both single dose anddose response studies.

f. Reference Compounds

Trimegestone and medroxyprogesterone acetate (MPA) are referenceprogestins and RU486 is the reference antiprogestin. All referencecompounds are run in full dose-response curves and the EC₅₀ or IC₅₀values are calculated.

TABLE 4 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for individual studies EC₅₀ 95% CI Compound Exp (nM) SElower upper Trimegestone 1 0.017 0.003 0.007 0.040 2 0.014 0.001 0.0110.017 3 0.019 0.001 0.016 0.024 MPA 1 0.019 0.001 0.013 0.027 2 0.0170.001 0.011 0.024

TABLE 5 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU486 IC₅₀ 95% CI Compound Exp. (nM) SE lower upperRU486 1 0.011 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 3 0.018 0.0010.014 0.022

EC₅₀: Concentration of a compound that gives half-maximal increase inBrdU incorporation with SE; IC₅₀: Concentration of a compound that giveshalf-maximal decrease in 0.1 trimegestone induced BrdU incorporationwith SE

4. T47D Cell Alkaline Phosphatase Assay

The purpose of this assay is to identify progestins or antiprogestins bydetermining a compound's effect on alkaline phosphatase activity in T47Dcells. The materials and methods used in this assay are as follows.

a. Culture Medium

DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 5% (v/v) charcoal strippedfetal bovine serum (not heat-inactivated), 100 U/ml penicillin, 100μg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).

b. Alkaline Phosphatase Assay Buffer

I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100

II. 0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl phosphate(Sigma).

c. Cell Culture and Treatment

Frozen T47D cells were thawed in a 37° C. water bath and diluted to280,000 cells/ml in culture medium To each well in a 96-well plate(Falcon, Becton Dickinson Labware), 180 μl of diluted cell suspensionwas added. Twenty μl of reference or test compounds diluted in theculture medium was then added to each well. When testing for progestinantagonist activity, reference antiprogestins or test compounds wereadded in the presence of 1 nM progesterone. The cells were incubated at37° C. in a 5% CO₂/humidified atmosphere for 24 hr.

d. Alkaline Phosphatase Enzyme Assay

At the end of treatment, the medium was removed from the plate and fiftyμl of assay buffer I was added to each well. The plates were shaken in atiter plate shaker for 15 min. Then 150 μl of assay buffer II was addedto each well. Optical density measurements were taken at 5 min intervalsfor 30 min at a test wavelength of 405 nM.

e. Analysis of Results

Analysis of dose-response data

For reference and test compounds, a dose response curve is generated fordose (X-axis) vs. the rate of enzyme reaction (slope) (Y-axis). Squareroot-transformed data are used for analysis of variance and nonlineardose response curve fitting for both agonist and antagonist modes. Huberweighting is used to downweight the effects of outliers. EC₅₀ or IC₅₀values are calculated from the retransformed values. JMP software (SASInstitute, Inc.) is used for both one-way analysis of variance andnon-linear dose response analyses in both single dose and dose responsestudies.

f. Reference Compounds

Progesterone and trimegestone are reference progestins and RU486 is thereference antiprogestin. All reference compounds are run in full doseresponse curves and the EC₅₀ or IC₅₀ values are calculated.

TABLE 6 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three independentexperiments EC50 95% CI Compound Exp (nM) SE lower upper Progesterone 10.839 0.030 0.706 0.996 2 0.639 0.006 0.611 0.669 3 1.286 0.029 1.1581.429 Trimegestone 1 0.084 0.002 0.076 0.091 2 0.076 0.001 0.072 0.080 30.160 0.004 0.141 0.181

TABLE 7 Estimated IC₅₀, standard error, and 95% confident interval forthe reference antiprogestin RU486 from three independent experiments IC50 95% CI Compound Exp. (nM) SE lower upper RU486 1 0.103 0.002 0.0920.115 2 0.120 0.001 0.115 0.126 3 0.094 0.007 0.066 0.134

B. In-vivo Biology

The primary in-vivo assay is the rat decidualization model which may beused to determine progestational effects of both agonists andantagonists. The secondary in-vivo assay is the rat ovulation inhibitionmodel which is under development and hence the protocol is un-available.

1. Rat Decidualization Assay

The objective of this procedure is used to evaluate the effect ofprogestins and antiprogestins on rat uterine decidualization and comparethe relative potencies of various test compounds. The materials andmethods used in this assay are as follows.

a. Methods

Test compounds are dissolved in 100% ethanol and mixed with corn oil(vehicle). Stock solutions of the test compounds in oil (Mazola™) arethen prepared by heating (˜80° C.) the mixture to evaporate ethanol.Test compounds are subsequently diluted with 100% corn oil or 10%ethanol in corn oil prior to the treatment of animals. No difference indecidual response was found when these two vehicles were compared.

b. Animals (RACUC Protocol #5002)

Ovariectomized mature female Sprague-Dawley rats (˜60-day old and 230 g)are obtained from Taconic (Taconic Farms, N.Y.) following surgery.Ovariectomy is performed at least 10 days prior to treatment to reducecirculating sex steroids. Animals are housed under 12 hr light/darkcycle and given standard rat chow and water ad libitum.

c. Treatment

Rats are weighed and randomly assigned to groups of 4 or 5 beforetreatment. Test compounds in 0.2 ml vehicle are administered bysubcutaneous injection in the nape of the neck or by gavage using 0.5ml. The animals are treated once daily for seven days. For testingantiprogestins, animals are given the test compounds and a EC₅₀ dose ofprogesterone (5.6 mg/kg) during the first three days of treatment.Following decidual stimulation, animals continue to receive progesteroneuntil necropsy four days later.

d. Dosing

Doses are prepared based upon mg/kg mean group body weight. In allstudies, a control group receiving vehicle is included. Determination ofdose-response curves is carried out using doses with half log increases(e.g. 0.1, 0.3, 1.0, 3.0 mg/kg . . . ).

e. Decidual Induction

Approximately 24 hr after the third injection, decidualization isinduced in one of the uterine horns by scratching the antimesometrialluminal epithelium with a blunt 21 G needle. The contralateral horn isnot scratched and serves as an unstimulated control. Approximately 24 hrfollowing the final treatment, rats are sacrificed by CO₂ asphyxiationand body weight measured. Uteri are removed and trimmed of fat.Decidualized (D-horn) and control (C-horn) uterine horns are weighedseparately.

f. Analysis of Results

The increase in weight of the decidualized uterine horn is calculated byD-horn/C-horn and logarithmic transformation is used to maximizenormality and homogeneity of variance. The Huber M-estimator is used todown weight the outlying transformed observations for both dose-responsecurve fitting and one-way analysis of variance. JMP software (SASInstitute, Inc.) is used for both one-way ANOVA and non-lineardose-response analyses.

g. Reference Compounds

All progestin reference compounds were run in full dose-response curvesand the EC₅₀ for uterine wet weight were calculated.

TABLE 8 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals for individual studies EC₅₀ 95% CI Compound Exp (mg/kg, s.c.)SE lower upper Progesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.763-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25 3 0.060.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12 0.02 0.090.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1 0.42 0.03 0.290.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61

TABLE 9 Estimated average EC₅₀, standard error, and 95% confidenceintervals for dose-response curves of 3 reference compounds EC50 95% CICompound (mg/kg, s.c.) SE lower upper Progesterone 5.62 0.62 4.55 7.003-Ketodesogestrel 0.10 0.02 0.07 0.14 Levonorgestrel 0.10 0.01 0.08 0.12

TABLE 10 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU 486 IC₅₀ 95% CI Compound Exp. (mg/kg, p.o.) SElower upper RU 486 1 0.21 0.07 0.05 0.96 2 0.14 0.02 0.08 0.27

Concentration: Compound concentration in assay(default-mg/kg bodyweight)

Route of administration: Route the compound is administered to theanimals

Body weight: Mean total animal body weight (default-kg)

D-horn: Wet weight of decidualized uterine horn (default-mg)

C-horn: Wet weight of control uterine horn (default-mg)

Decidual response: [(D-C)/C]×100%

Progestational activity: Compounds that induce decidualizationsignificantly (p<0.05) compared to vehicle control are considered active

Antiprogestational activity: Compounds that decrease EC₅₀ progesteroneinduced decidualization significantly (p<0.05)

EC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal increase in decidual response (default-mg/kg)

IC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal decrease in EC₅₀ progesterone induced decidual response(default-mg/kg)

EXAMPLE 1226-(3-Methoxyphenyl)spiro[4H-3,1-benzoxazin-4,1-cyclobutan]-2(1H)-one

A solution of Boc protected 4-chloroaniline (1.15 g, 5 mmol) inanhydrous THF was treated at −78° C. under a blanket of nitrogen witht-butyllithium (7.4 mL, 12.5 mmol). The reaction solution was thenslowly warmed to −20° C., kept stirring for 1.5 hours, and treated withcyclobutanone (1 mL, 13.4 mmol). The mixture was warmed to rt andquenched with brine (30 mL) and 1N aqueous hydrogen chloride solution(10 mL) was added Ethyl acetate was added and the organic layer wasseparated and dried (MgSO₄). After removal of the solvent, the residuewas purified by flash column chromatography (hexane:ethyl acetate/3:1)to give the alcohol which was used in next step without furtherpurification.

To a solution of above product in ethanol was added potassium hydroxide(2 g). The reaction mixture was stirred at rt for 18 hours, followed bythe addition of brine (20 mL) and a cold 1N aqueous hydrogen chloridesolution (20 mL). The precipitate was collected on a filter and washedwith water to afford6-chlorospiro[4H-3,1-benzoxazine-4,1-cyclobutan]-2(1H)-one as a whitesolid (0.13 g, 12% for two steps): mp 183-184° C.; MS (ESI) m/z 222[M−H]⁻.

A mixture of 6-chlorospiro[4H-3,1-benzoxazine-4,1-cyclobutan]-2(1H)-one(0.1 g, 0.45 mmol), 3-methoxyphenyl boronic acid (0.1 g, 0.66 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloronickel (II) (50 mg, 0.073mmol), potassium phosphate (0.35 g, 1.7 mmol) in dioxane (5 mL) wasdegassed to remove oxygen and then heated at 85° C. under a blanket ofnitrogen for 72 hours. The reaction mixture was allowed to cool to rt.Ethyl acetate (30 mL) and brine (20 mL) were added. The organic layerwas separated and dried (MgSO₄). After removal of solvent, the residuewas purified using column chromatography (hexane:ethyl acetate/3:1) toyield6-(3-methoxy-phenyl)spiro[4H-3,1-benzoxazine-4,1-cyclobutan]-2(1H)-oneas white solid (18 mg, 14%): mp 145-146° C.; ¹H-NMR (DMSO-d₆) δ8.04 (s,1H), 7.69 (d, 1H, J=1.6 Hz), 7.59 (dd, 1H, J=8.2, 1.5 Hz), 7.36 (d, 1H,J=7.9 Hz), 7.27 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=2.2 Hz), 6.99 (d, 1H,J=8.2 Hz), 6.92 (dd, 1H, J=8.0, 2.4 Hz), 3.83 (s, 3H), 2.45-2.62(m, 4H),1.81-2.12 (m, 2H) ); MS ((+)APCI) m/z 296 [M+H]⁺.

EXAMPLE 1238-Bromo-6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a mixture of6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one(0.2 g, 0.65 mmol) and sodium acetate (0.1 g, 1.2 mmol) in acetic acid(5 mL) was added, at rt under nitrogen bromine (0.04 mL, 0.78 mmol). Thereaction mixture was stirred for 20 hours and poured into ice water (30mL). The precipitate was collected on a filter and washed with water(3×5 mL) to yield8-bromo-6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-oneas off-white solid (0.18, 72%): mp 194-195° C.; ¹H-NMR (DMSO-d₆) δ9.77(s, 1H), 8.02 (dd, 1H, J=7.10, 1.81 Hz), 7.92 (s, 1H), 7.77 (m, 1H),7.66 (s, 1H), 7.47-7.53 (m, 1H), 1.71 (s, 6H). MS (ESI) m/z 384, 386[M−H]⁻.

EXAMPLE 1243-(8-Bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile

Prepared according to the above procedure from3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile(0.5 g, 1.7 mmol) as an off-white solid (0.48 g, 75%): mp 216-217° C.;¹H-NMR (DMSO-d₆) δ9.78 (s, 1H), 8.18 (t, 1H, J=1.6 Hz), 8.02-8.08 (m,2H), 7.81 (m, 1H), 7.75 (d, 1H, J=1.8 Hz), 1.66 (s, 6H). MS (ESI) m/z373, 375 [M−H]⁻.

EXAMPLE 1255-(8-Bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile

Prepared according to the above procedure from5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile(0.2 g, 0.67 mmol) as an off-white solid (0.18 g, 72%): mp 235-236° C.;¹H-NMR (DMSO-d₆) δ9.78 (s, 1H), 8.38 (dd, 1H, J=6.1, 2.4 Hz), 8.14-8.20(m, 1H), 7.98 (d, 1H, J=1.9 Hz), 7.71 (d, 1H, J=1.8 Hz), 7.62 (t, 1H,J=9.1 Hz), 1.69 (s, 6H). MS (ESI) m/z 373, 375 [M−H]⁻.

EXAMPLE 1266-(3-Bromophenyl)-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of6-(3-bromophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1 g,3.0 mmol) in anhydrous DMF was added, at rt under a blanket of nitrogen,sodium hydride (60% in mineral oil, 0.24 g, 6.0 mmol). After stirringfor 20 minutes, the reaction solution was treated with iodomethane andstirred for 1.5 hours. The mixture was poured into a saturated aqueousammonium sulfate solution (40 mL) and ethyl acetate (40 mL) was added.The organic layer was separated, dried (MgSO₄), and evaporated to yield6-(3-bromophenyl)-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one asoff-white solid (0.75 g, 72%): mp 142-143° C.; ¹H-NMR (DMSO-d₆) δ7.93(s, 1H), 7.71 (m, 1H), 7.65 (s, 1H), 7.55 (d, 1H, J=8.0 Hz), 7.42 (t 1H,J=7.7 Hz), 7.18 (d, 1H, J=8.4 Hz), 3.35 (s, 3H), 1.67 (s, 6H). MS (ESI)m/z 368, 370 [M+Na]⁺.

EXAMPLE 1276-(3-Fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

4-Amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile was prepared from3-fluorophenyl boronic acid and 2-amino-5-bromobenzonitrile according toprocedure A. A solution of4-amino-3′-fluoro[1,1′-biphenyl]-3-carbonitrile (6.65 g, 31.3 mmol) inanhydrous THF (100 mL) was treated drop wise at rt under nitrogen withmethylmagnesium bromide (3.0 M in ether, 21 mL, 63 mmol). Afteraddition, the reaction mixture was heated at gentle reflux for 1.5hours, cooled to rt, and treated with 3N aqueous hydrogen chloridesolution (30 mL). The mixture was heated at reflux for 3 hours, cooledto ambient temperature, and adjusted to pH 5-6 by addition of asaturated aqueous sodium carbonate solution. Ethyl acetate (100 mL) wasadded, organic layer was separated and aqueous layer was extracted withethyl acetate (3×50 mL). The combined organic layers were dried (MgSO₄)and evaporated. The residue was purified by a silica gel columnchromatography (hexane:ethyl acetate/3:1) to afford1-(4-amino-3′-fluoro[1,1′-biphenyl]-3-yl)ethanone (3.1 g, 43%): mp156-157° C.

A solution of 1-(4-amino-3′-fluoro[1,1′-biphenyl]-3-yl)ethanone (3 g, 13mmol) in anhydrous methanol (60 mL) was treated at rt under nitrogenwith sodium borohydride in a portion wise manner. Alter addition, thereaction mixture was stirred for 4 hours, treated with a saturatedaqueous ammonium sulfate solution (50 mL) and ethyl acetate (100 mL).The organic layer was separated, dried (MgSO₄) and evaporated. Theresidue was purified on a silica gel column chromatography (hexane:ethylacetate/3:1) to yield 1-(4-amino-3′-fluoro[1,1′-biphenyl]-3-yl)ethanolas a white solid (2 g, 67%): mp 136-137° C.

A mixture of above alcohol (0.2 g, 0.87 mmol) and triphosgene inanhydrous THF (20 mL) was stirred at rt under nitrogen. After 15minutes, the mixture was treated with a saturated aqueous sodiumbicarbonate solution (30 mL) and ethyl acetate (40 mL). The organiclayer was separated, dried (MgSO₄), and evaporated to give6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as awhite solid (0.18 g, 81%): mp 160-161° C.; ¹H-NMR (DMSO-d₆) δ10.31 (s,1H), 7.62 (dd, 1H, J=8.2, 1.9 Hz), 7.57 (s, 1H), 7.44-7.53 (m, 3H),7.13-7.20 (m 1H), 6.97 (d, 1H, J=8.2 Hz), 5.57 (q, 1H, J=6.6 Hz), 1.63(d, 3H, J=6.6 Hz). MS (ESI) m/z 256 [M−H]⁻.

EXAMPLE 1283-(4,4-Dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile

To a solution of 2-amino-3-methoxybenzoic acid (5 g, 30 mmol) inanhydrous THF (100 mL) was added at ambient temperature under a blanketof nitrogen methylmagnesium bromide (3.0 M in THF, 50 mL, 150 mmol). Thereaction mixture was heated at 50° C. for 18 hours, cooled to rt, andtreated with a saturated aqueous ammonium chloride solution (50 mL).Ethyl acetate (100 mL) was added and organic layer was separated, dried(MgSO₄), and evaporated. The residue was dissolved in anhydrous THF (100mL) and treated at ambient temperature under nitrogen with1,1′-carbonyldiimidazole (5.4 g, 33 mmol). After 24 hours, the mixturewas quenched with 1N aqueous hydrogen chloride solution (30 mL). Ethylacetate (100 mL) was added, organic layer was separated, dried (MgSO₄),and evaporated. The residue was purified by a silica gel columnchromatography (hexane:ethyl acetate/3:1) to afford8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as whitesolid (3.5 g, 56%): MS (ESI) m/z 208 [M+H]⁺.

To a mixture of8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.1 g, 10.1mmol), sodium acetate (1.5 g, 18 mmol) in acetic acid (30 mL) was addedbromine (0.62 mL, 12 mmol) at ambient temperature. After 30 minutes, thesolution was treated with a concentrated ammonium hydroxide solution (50mL). The precipitate was collected on a filter and washed with water(3×20 mL) to yield6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.7g, 93%) as off-white solid: MS (ESI) m/z 286, 288 [M+H]⁺.

A mixture of6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassiumacetate (1.5 g, 15.3 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1complex with methylene chloride, 0.5 g, 0.6 mmol) in DMF (30 mL) wassubject to a positive flow of nitrogen to remove oxygen and then heatedat 85° C. under a blanket of nitrogen for 18 hours. The reaction mixturewas allowed to cool to ambient temperature, treated with3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) chloride (1:1complex with methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate(2 g, 19 mmol) in water (10 mL). The resulted solution was heated at 85°C. for 3 hours under a blanket of nitrogen, cooled to rt, and treatedwith brine (50 mL). Ethyl acetate (100 mL) was added, organic layer wasseparated, dried (MgSO₄), and evaporated. The residue was purified by aflash silica gel column chromatography (THF:hexane/2:3) to yield3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrileas a white solid (0.6 g, 33%): mp 252-253° C.; ¹H-NMR (DMSO-d₆) δ9.76(s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6 Hz), 7.82 (m, 1H), 7.39 (s1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z 325 [M−H]⁻.

EXAMPLE 1293-(4,4-Dimethyl-8-hydroxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile

A mixture of3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile(0.1 g, 0.31 mmol), Lithium iodide (0.3 g, 2.24 mmol) in 2,4,6-collidinewas heated at reflux under nitrogen for 5 hours. The solvent was removedin vacuo and the residue was taken in a mixture of brine (10 mL) andethyl acetate (30 mL). The organic layer was separated, dried (MgSO₄),and evaporated. The resultant residue was purified on a silica gelcolumn chromatography (hexane:ethyl acetate/1:1) to give the titlecompound as white plates (0.03 mg, 31%): mp 197-198° C.; ¹H-NMR(DMSO-d₆) δ10.16 (s, 1H), 9.55 (s, 1H), 8.01 (s, 1H), 7.79-7.87 (m, 2H),7.20 (s, 1H), 7.08 (d, 1H, J=1.0 Hz), 1.65 (s, 6H). MS (ESI) m/z 311[M−H]⁻.

EXAMPLE 1306-(2,3-Difluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared according to procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and2,3-difluorobenzyltriflate. A yellow solid: mp 166-167° C.; ¹H-NMR(DMSO-d₆) δ10.4 (s, 1H), 7.5-7.2 (m, 5H), 7.0 (m, 1H), 1.7 (s, 6H); MS(EI) m/z 289 ([M+H]⁺); Anal. Calc. For C₁₆H₁₃F₂NO₂: C, 66.43; H, 4.53;N, 4.84. Found: C, 66.15; H, 4.37; N, 4.64.

EXAMPLE 1313-(1-Ethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3oxazin-6-yl)-5-fluoro-benzonitrile

Prepared according to the procedure for example 125 from3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile.A white solid: mp 154-155° C.; ¹H-NMR (DMSO-d₆) δ8.17 (s, 1H), 8.03 (d,1H, J=10.5 Hz), 7.84-7.77 (m, 3H), 7.27 (d, 1H, J=8.54 Hz), 3.97 (q, 2H,J=6.89 Hz), 1.67 (s, 6H) 1.21 (t, 3H, J=6.95 Hz); MS (EI) m/z 324([M+H]⁺); Anal. Calc. For C₁₉H₁₇FN₂O₂: C, 70.36; H, 5.28; N, 8.64.Found: C, 70.33; H, 5.51; N, 8.48.

EXAMPLE 132[6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2yl]acetonitrile

Prepared according to procedure B from(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and(6-bromo-2-pyridyl)acetonitrile (J. Org. Chem. 1988, 53, 786-790). Anoff-white solid, mp 210-212.5° C. ¹H NMR (DMSO-d₆) δ1.68 (s, 6H), 4.27(s, 2H), 7.00 (d, 1H, J=8.3 Hz), 7.34 (d, 1H, J=7.1 Hz), 7.89-7.96 (m,2H), 8.00-8.05 (m, 2H), 10.42 (s, 1H). MS (ESI) [M−H]⁻=292. Anal. calcd.for C₁₇H₁₅N₃O₂: C, 69.61; H, 5.15; N, 14.33. Found: C, 68.49; H, 5.19;N, 13.74.

EXAMPLE 1333-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d]1,3]-oxazin-6-yl)-5-fluoro-phenylacetonitrile

To a solution of 3-bromo-5-fluorobenzaldehyde(22.25 g, 0.11 mole) inmethanol at rt was added NaBH₄, (2.07 g, 0.055 mole) stirred at rt for 2hr. The reaction was quenched with H₂O, and concentrated. The residuewas diluted with diethyl ether, washed with 1 N HCl, brine, dried overMgSO₄, concentrated. 3-Bromo-5-fluorobenzyl alcohol as a colorless oilwas collected (14.6 g, 65%). ¹H NMR(DMSO-d₆) δ4.50 (m, 2H), 5.44 (t, 3H,J=5.93 Hz), 7.16 (dd, 1H, J=1.09, 8.79 Hz), 7.36 (s, 1H), 7.38 (dd, 1H,J=2.99, 6.15 Hz); Anal. Calc. For C₇H₆Br₂FO: C, 41.01; H, 2.95. Found:C, 41.30; H, 3.01.

To a solution of 3-Bromo-5-fluorobenzyl alcohol (2.3 g, 0.011 mole) inCH₂Cl₂ (15 mL) was added 12.4 mL of 1.0 M PBr₃ (3.33 g, 0.0123 mole) inCH₂Cl₂, stirred for 3 hr, diluted with ether (100 mL), washed with H₂O(50 ml, 3×), dried over MgSO₄, concentrated, and purified by columnchromatography using 1:9 ethyl acetate/hexane as an eluant solventsystem. 3-Bromo-5-fluorobenzyl bromide as a white crystalline materialwas obtained, mp 41-43° C. ¹H NMR (DMSO-d₆) δ4.69 (s, 2H), 7.52 (d, 1H,J=1.76 Hz) 7.54 (d, 1H, J=1.91 Hz), 7.56 (s, 1H); MS(EI): M+. m/z 266;Anal. Calc. For C₇H₅Br₂F: C, 31.38; H, 1.88. Found: C, 31.75; H, 1.78.

To a solution of 3-bromo-5-fluorobenzyl bromide (3.2 g, 0.0112 mole) in1,4-dioxane (20 mL) was added a solution of KCN (0.82 g, 0.013 mole) inH₂O (5 mL) and EtOH (5 mL), refluxed for 2 hours, and extracted withether, washed with brine, dried over MgSO₄, and concentrated. Columnchromatography was performed using hexane/ethyl acetate (19:1).3-Bromo-5-fluorophenylacetonitrile was obtained was a colorless oil: ¹HNMR (DMSO-d₆) δ4.15 (s, 2H), 7.29 (d, 1H, J=9.37 Hz), 7.47 (s, 1H), 7.55(d, 1H, J=8.45 Hz); MS(EI) M+m/z 213; Anal. Calc. For C₈H₅BrFN: C,44.89; H, 2.35; N, 6.54. Found: C, 44.88; H, 2.32; N, 6.46.

The title compound was prepared according to the procedure B from3-bromo-5-fluorophenylacetonitrile and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Awhite solid was obtained and recrystallized from ethanol/ether: mp218-220. ¹H NMR (DMSO-d₆) δ1.67 (s, 6H), 4.11(s, 2H), 6.98 (d, 1H,J=8.92 Hz), 7.18 (d, 1H, J=9.26 Hz), 7.52-7.62 (m, 3H), 10.37 (s, 1H);MS(EI) (M−H)⁻ m/z 309; Anal. Calcd. For C₁₈H₁₅FN₂O₂: C, 69.67; H, 4.87;N, 9.03. Found: C, 69.78; H, 4.97; N, 8.36.

EXAMPLE 1343-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)-4-fluoro-phenylacetonitrile

To a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mole) in CCl₄ (150mL) was added NBS (14.2 g, 0.080 mole). The resulting reaction solutionwas heated under reflux with the starting material being completelyconsumed within 2 hr. CCl₄ was removed under reduced pressure and theresidue was diluted, dissolved in ether, washed with brine (3×), driedover MgSO₄, and concentrated. Chromatography using hexane yielded5-bromo-2-fluorobenzyl bromide. The product was immediately used for thereaction below.

5-Bromo-2-fluorobenzyl bromide (8.0 g, 0.03 mole) was dissolved in1,4-Dioxane (60 mL) and added to a solution of KCN (2.04 g, 0.031 mole)in H₂O (20 mL) and ethanol (20 mL). The resulting mixture was heatedunder reflux for 5 h. After cooling to rt, the product was extractedwith ether (200 mL), washed with brine, dried over MgSO₄, concentrated.Crystallized from ether/hexane to give5-bromo-2-fluorophenylacetonitrile as a white crystalline material (5.6g, 88%): mp 55-58° C.; ¹H NMR (DMSO-d₆) δ4.07 (s, 2H), 7.29 (t, 1H,J=9.23 Hz), 7.60-7.69 (m, 2H); MS (EI) M+. m/z 213; Anal. Calc. ForC₈H₅Br₂FN: C, 44.89; H, 2.35; N, 6.54. Found: C, 44.90; H, 2.24; N,6.43.

The title compound was prepared from 5-Bromo-2-fluorophenylacetonitrileand (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxaxin-6-yl)boronic acid.White solid; mp 184-187° C.; ¹H NMR (DMSO-d₆) δ1.67 (s, 6H), 4.11 (s,2H), 6.98 (d, 1H, J=8.92 Hz), 7.36 (t, 1H, J=9.13 Hz) 7.54 (d, 2H,J=7.91 Hz), 7.67-7.75 (m, 2H), 10.37 (s, 1H); MS(EI) (M−H)⁻ m/z 309;Anal. Calc. For C₁₈H₁₅FN₂O₂: C, 69.67; H, 4.87; N, 9.03. Found: C,68.71; H, 4.80; N, 8.54.

EXAMPLE 1354-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluorophenylacetonitrile

Prepared according to procedure B from4-bromo-2-fluorophenylacetonitrile (T. Alessi A. H. P. U.S. Pat. No.4,895,862) and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Agrey solid; mp 253-256° C. ¹H-NMR(DMSO-d₆) δ10.35 (s, 1H) 7.67-7.49 (m,5H), 6.97 (d, 1H; J=8.6 Hz) 4.09 (s, 2H) 1.67 (s, 6H); MS [M−H]⁻ m/z309. Anal. Calc. For C₁₈H₁₅N₂FO₂.0.15H₂O: C, 69.07; H, 4.93; N, 8.95.Found C, 69.27; H, 5.05; N, 8.50

EXAMPLE 136 2-(4,4-Dimethyl2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)phenylacetonitrile

Prepared according to procedure B from 2-bromophenylacetonitrile and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid.White solid; mp 176-179° C.; ¹H-NMR(DMSO-d₆), δ10.31 (s, 1H), 7.53 (m,1H), 7.48 (m, 2H), 7.22-7.32 (m, 3H), 6.98 (d, 1H, J=8.0 Hz), 3.90 (s,2H), 1.64 (s, 6H). MS (+)APCI [M+H]⁺ m/z=293. Anal. Calc. ForC₁₈H₁₆N₂O₂: C, 73.95; H, 5.52, N, 9.58. Found: C, 73.51; H, 5.70; N,9.39.

EXAMPLE 137N-[4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluoro-phenyl]-acetamide

Prepared according to procedure B from 4′-bromo-2′-fluoroacetanilide and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Offwhite solid; mp 245-247° C. ¹H-NMR (DMSO-d₆), δ10.3 (s, 1H), 9.79 (s,1H), 7.95 (t, 1H, J=8.4 Hz), 7.56-7.63 (m, 3H), 7.47 (dd, 1H, J=1.64,8.47 Hz), 6.95 (d, 1H, J=8.9 Hz), 2.1(s, 3H), 1.67 (s, 6H); MS+APCI[M+H]⁺ m/z 329. Anal. Calc. For C₁₈H₁₇N₂FO₃: C, 65.85; H, 5.22; N, 8.53.Found: C, 65.46; H, 5.24; N, 8.12.

EXAMPLE 1386-(3-Fluoro-4-methoxy-phenyl)4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared according to procedure B from 4-bromo-2-fluoroanisole and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid.White solid: mp 210-211° C. ¹H-NMR (DMSO-d₆), δ10.27 (s,1H), 7.52-7.60(m, 3H), 7.45(d, 1H, J=8.6 Hz), 7.22 (t, 1H, J=8.9 Hz), 6.94 (d, 1H,J=8.8 Hz), 3.87 (s, 3H), 1.66 (s, 6H). MS [M−H]⁻ m/z=300. Anal. Calc.For C₁₇H16FNO₃: C, 67.76; H, 5.35; N, 4.65. Found: C, 67.88; H, 5.39; N,4.70.

EXAMPLE 1393-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)phenylacetonitrile

Prepared according to the procedure B from 3-bromophenylacetonitrile and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid.White solid: mp 188-190° C. ¹H-NMR (DMSO-d₆) δ10.33 (s, 1H), 7.62 (m,2H), 7.55 (m, 2H), 7.48 (d, 1H, J=8.00 Hz), 7.33 (d, 1H, J=7.57 Hz),6.99 (d, 1H, J=8.81 Hz) 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291(M−H).Anal. Calc. For (C₁₈H₁₆N₂O₂)₂.0.3 H₂O: C, 72.61; H, 5.62; N, 9.41.Found: C, 73.00; H, 5.43; N, 8.81

EXAMPLE 1403-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)benzenesulfonamide

Prepared according to procedure B from 3-bromobenzenesulfonamide and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid.White solid: mp 242-244° C. (dec) ¹H-NMR (DMSO-d₆) δ10.28 (s, broad 1H),8.07 (s, 1H), 7.9 (d, 1H, J=7.80 Hz), 7.78 (d, 1H, J=7.86 Hz), 7.64 (t,1H, J=7.79 Hz), 7,59 (m, 2H), 7.42 s, broad 2H), 7.02 (d, 1H, J=8.86Hz), 1.68 (s, 6H); MS m/z 331(M+H). Anal. Calc. For C₁₆H₁₆N₂O₄S: C,57.82; H, 4.85; N, 8.43. Found: C, 57.49; H, 5.08; N, 8.05.

EXAMPLE 141(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)-thiophene-2-sulfonamide

Prepared according to procedure B from 5-bromothiophene-2-sulphonamideand (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid.White solid: mp 258-260° C., ¹H-NMR (DMSO-d₆) δ10.41 (s, 1H), 7.71 (s,2H), 7.58 (m, 2H), 7.52 (d, 1H, J=3.9 Hz), 7.48 (d, 1H J=8.16 Hz),6.95(d, 1H J=8.16), 1.66 (s, 6H); MS m/z 337 (M−H). Anal. Calc. ForC₁₄H₁₄N₂O₄S₂: C, 49.69; H, 4.17; N, 8.28. Found: C, 49.90; H, 4.28; N,8.12.

EXAMPLE 1426-(6-Amino-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazine-2-one

Prepared according to procedure B from 2-amino-5-bromopyridine and(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid.White crystals, mp 257-259° C. ¹H-NMR (DMSO-d₆) δ10.20 (s, 1H), 8.22 (d,1H, J=2.38 Hz) 7.69, 7.66 (dd, 1H, J=2.5, 2.5 Hz), 7.42 (m, 2H), 6.89(d, 1H, J=8.8 Hz), 6.49(d, 1H, J=8.64 Hz), 6.02 (s, 2H), 1.64 (s, 6H);MS m/z 269 M⁺. Anal. Calcd. For C₁₅H₅N₃O₂.17H₂O: C, 66.15; H, 5.68; N,15.43. Found: C, 66.10; H, 5.81; N, 15.02.

EXAMPLE 1436-(5-Diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

Prepared according to procedure B from 4,4-dimethyl 2 oxo -1,4-dihydro2H-benzo [d][1,3]oxazine-6-boronic acid and 3-bromo-5-diethoxymeyhylfuran. A brown gum: ¹H NMR (DMSO-d₆) δ10.2 (s, 1H), 8.12(s, 1H),7.54-7.49 (m, 2H), 6.93-6.88 (m, 2H), 5.56 (s, 1H), 3.60-3.38 (m, 4H),1.67 (s, 6H), 1.2-1.14 (m, 6H). .MS (ESI) m/z 344 [M−H]⁻. Anal. Calcd.For C₁₉H₂₃NO₅ 1/2H₂O: C, 64.39; H, 6.77; N, 3.95. Found C, 64.90; H,6.79; N, 3.78.

EXAMPLE 1444-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde

A solution of6-(5-diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one(1.1 g, 3 mmol) was stirred in THF (20 mL) and 2N HCl (2 mL) for 1 hour.The crystalline product was filtered and dried (0.52 g, 69%): mp262-263° C.; ¹H NMR (DMSO-d₆) δ10.3 (s, 1H), 9.65 (s, 1H), 8.59 (s, 1H),8.04 (s, 1H), 7.65-7.64 (d, 1H, J=1.5 Hz), 7.61-7.60 (d, 1H, J=1.8 Hz),7.59-7.58 (d, 1H, J=1.8 Hz), 6.94-6.91 (d, 1H, J=8.2 Hz), 1.65 (s, 6H).MS (ESI) m/z 270 [M−H]⁻.

EXAMPLE 1454-(1,4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)-2-furancarboxaldehydeoxime

A mixture of4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde(2.7 g, 10 mmol), hydroxylamine hydrochloride (0.75 g, 10.6 mmol) andsodium acetate (0.87 g, 10.6 mmol) was heated at reflux in 80% ethanol(25 mL) for 2 hours. The title compound crystallized from the cooledreaction mixture as tan crystals (1.5 g, 52.4%): mp 236-238° C. ¹H NMR(DMSO-d₆) δ11.97 (s, 1H), 10.26 (s, 1H), 8.2 (s, 1H), 7.63 (s, 1H),7.56-7.52 (m, 3H), 6.91-6.88 (d, 1H, J=8.1 Hz), 1.66 (s, 6H). MS ESI m/z285 [M−H]⁻. Anal. Calcd. For C₁₅H₁₄N₂; O₄: C, 62.93; H, 4.93; N, 9.79.Found C, 62.77; H, 5.00; N, 9.79.

All publications cited in this specification are incorporated herein byreference herein. While the invention has been described with referenceto a particularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

What is claimed:
 1. A method of contraception which comprisesadministering to a female of child bearing age over a period of 28consecutive days: a) a first phase of from 18 to 21 daily dosage unitscontaining a progestational agent at a daily dose equal inprogestational activity to from about 35 to about 150 μg levonorgestreland ethinyl estradiol at a daily dose range of from about 10 to about 35μg; b) a second phase of from 1 to 7 daily dosage units, each dailydosage unit containing an antiprogestin of the formula:

 wherein: R¹ and R² are independent substituents selected from the groupconsisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^(A),and NR^(B)COR^(A); or R¹ and R² are fused to form: (i) a carbon-based 3to 8 membered saturated spirocyclic ring; (ii) a carbon-based 3 to 8membered spirocyclic ring having in its backbone one or morecarbon-carbon double bonds; or (iii) a 3 to 8 membered heterocyclic ringhaving in its backbone one to three heteroatoms selected from the groupconsisting of O, S and N; the spirocyclic rings of (i), (ii) and (iii)being optionally substituted by from 1 to 4 groups selected from thegroup consisting of fluorine, C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆thioalkyl, CF₃, OH, CN, NH₂, NH(C₁ to C₆ alkyl), and N(C₁ to C₆ alkyl)₂;R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(B) is H, C₁ to C₃alkyl, or substituted C₁ to C₃ alkyl; R³ is H, OH, NH₂, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, substituted C₃ to C₆alkenyl, alkynyl, substituted alkynyl, or COR^(C); R^(C) is H, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substitutedC₁ to C₃ aminoalkyl; R⁴ is H, halogen, CN, NO₂, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, alkynyl, substituted alkynyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ aminoalkyl, orsubstituted C₁ to C₆ aminoalkyl; R⁵ is (iv), (v), (vi), or (vii) (iv) asubstituted benzene ring having the substituents X, Y and Z:

 wherein: X is selected from the group consisting of halogen, CN, C₁ toC₃ alkyl, substituted C₁ to C₃ alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkoxy, substituted C₁ to C₃ thioalkoxy, amino, C₁to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone1 to 3 heteroatoms, COR^(D), OCOR^(D), and NR^(E)COR^(D); R^(D) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl; Y and Z are independent substituentsselected from the group consisting of H, halogen, CN, NO₂, amino,aminoalkyl, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkoxy;(v) a five membered ring having in its backbone 1, 2, or 3 heteroatomsselected from the group consisting of O, S, SO, and SO₂ and having oneor two independent substituents selected from the group consisting of H,halogen, CN, NO₂, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(F), and NR^(G)COR^(F); (vi) a five membered ring havingin its backbone 1, 2, or 3 NR⁶ heteroatoms and having one or twoindependent substituents selected from the group consisting of H,halogen, NO₂, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(F), and NR^(G)COR^(F); or (vii) a six membered ringhaving in its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂, and NR⁶ and having one or two independentsubstituents selected from the group consisting of H, halogen, CN, NO₂,amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(F),and NR^(G)COR^(F); R^(F) is H, C₁ to C₃ alkyl, substituted C₁ to C₃alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(G)is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R⁶ is H or C₁ to C₃alkyl; or pharmaceutically acceptable salt thereof; at a concentrationof from 2 to 50 mg and ethinyl estradiol at a concentration of fromabout 10 to about 35 μg; and c) optionally, a third phase of dailydosage units of an orally and pharmaceutically acceptable placebo, thetotal of the daily dosage units being
 28. 2. The method according toclaim 1, wherein the progestational agent is levonorgestrel and wherein:R¹ is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heterocyclic, substituted heterocyclic, COR^(A), or NR^(B)COR^(A); R² isH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, COR^(A), or NR^(B)COR^(A); R⁴ is H, halogen, CN, NO₂, C₁to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁to C₆ alkoxy, amino, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆aminoalkyl; R⁵ is (viii), (ix), (x) or (xi): (viii) the substitutedbenzene ring (iv), wherein: X is selected from the group consisting ofhalogen, CN, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ thioalkoxy, substituted C₁to C₃ thioalkoxy, amino, C₁ to C₃ aminoalkyl, substituted C₁ to C₃aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heterocyclic ringcontaining in its backbone 1 to 3 heteroatoms, COR^(D), OCOR^(D), andNR^(E)COR^(D); Y and Z are independent substituents selected from thegroup consisting of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃alkyl, and C₁ to C₃ thioalkoxy; (ix) the five membered ring (v)containing one or two independent substituents selected from the groupconsisting of H, halogen, CN, NO₂, amino, C₁ to C₃ alkyl, and C₁ to C₃alkoxy; (x) the five membered ring (vi) containing one or twoindependent substituents selected from the group consisting of H,halogen, NO₂, amino, C₁ to C₃ alkyl, and C₁ to C₃ alkoxy; or (xi) thesix membered ring (vii) containing one or two independent substituentsselected from the group consisting of H, halogen, CN, NO₂, amino, C₁ toC₃ alkyl, and C₁ to C₃ alkoxy.
 3. The method according to claim 1,wherein the progestational agent is levonorgestrel and wherein: R¹ is H,C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, COR^(A), or NR^(B)COR^(A); R⁴ is H, halogen,CN, NO₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ aminoalkyl, or substitutedC₁ to C₆ aminoalkyl; R⁵ is (xii), (xiii), (xiv) or (xv): (xii) thesubstituted benzene ring (iv), wherein: X is selected from the groupconsisting of halogen, CN, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl,C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ thioalkoxy,substituted C₁ to C₃ thioalkoxy, amino, C₁ to C₃ aminoalkyl, substitutedC₁ to C₃ aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 memberedheterocyclic ring having in its backbone 1 to 3 heteroatoms, COR^(D),OCOR^(D), and NR^(E)COR^(D); Y and Z are independent substituentsselected from the group consisting of H, halogen, CN, NO₂, C₁ to C₃alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkoxy; (xiii) the fivemembered ring (v) containing one or two independent substituentsselected from the group consisting of H, halogen, CN, NO₂, amino, C₁ toC₃ alkyl, and C₁ to C₃ alkoxy; (xiv) the five membered ring (vi)containing one or two independent substituents selected from the groupconsisting of H, halogen, NO₂, amino, C₁ to C₃ alkyl, and C₁ to C₃alkoxy; or (xv) the six membered ring (vii) containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂, amino, C₁ to C₃ alkyl, and C₁ to C₃ alkoxy.
 4. Themethod according to claim 1, wherein the progestational agent islevonorgestrel and wherein: R¹=R² and are selected from the groupconsisting of C₁ to C₃ alkyl and substituted C₁ to C₃ alkyl; or R¹ andR² are fused to form the carbon-based 3 to 6 membered saturatedspirocyclic ring; R³ is H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, or COR^(C); R^(C) is H, C₁ to C₃ alkyl, or C₁ to C₃ alkoxy; R⁴ isH, halogen, CN, NO₂, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ toC₃ alkoxy, or substituted C₁ to C₃ alkoxy; R⁵ is (xvi), (xvii), (xviii),or (xix): (xvi) the substituted benzene ring (iv) of the structure:

 wherein: X is halogen, CN, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁ toC₃ perfluoroalkyl, 5 membered heterocyclic ring containing in itsbackbone 1 to 3 heteroatoms, or C₁ to C₃ thioalkoxy; Y is H, halogen,CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ to C₃ thioalkoxy; (xvii)the five membered ring (v) of the structure:

 wherein: U is O or S; X′ is selected from the group consisting ofhalogen, CN, NO₂, C₁ to C₃ alkyl and C₁ to C₃ alkoxy; Y′ is selectedfrom the group consisting of H and C₁ to C₃ alkyl; (xviii) the fivemembered ring (vi) of the structure:

 wherein: U is NR⁶; X′ is selected from the group consisting of halogen,NO₂, C₁ to C₃ alkyl and C₁ to C₃ alkoxy; Y′ is selected from the groupconsisting of H and C₁ to C₃ alkyl; or (xix) the six membered ring (vii)of the structure:

 wherein: X¹ is N or CX²; X² is halogen, CN, C₁ to C₃ alkoxy, or NO₂. 5.The method according to claim 1, wherein the progestational agent islevonorgestrel and wherein: R¹ and R² are CH₃ or R¹ and R² are fused toform the carbon-based 6 membered saturated spirocyclic ring R³ is H, OH,NH₂, CH₃, substituted CH₃, or COR^(A); R^(A) is H, C₁ to C₃ alkyl, or C₁to C₃ alkoxy; R⁴ is H, halogen, NO₂, CN, or C₁ to C₃ alkyl; R⁵ is thesubstituted benzene ring (iv) of the structure:

 wherein: X is selected from the group consisting of halogen, CN,methoxy, NO₂, or 5-membered heterocyclic ring; wherein said 5-memberedheterocyclic ring is 2-thiazole; Y is H or halogen; wherein said halogenis F.
 6. The method according to claim 1, wherein the progestationalagent is levonorgestrel and wherein: R¹ and R² are CH₃ or R¹ and R² arefused to form the carbon-based 6 membered saturated spirocyclic ring; R³is H, OH, NH₂, CH₃, substituted CH₃, or COR^(A); R^(A) is H, C₁ to C₃alkyl, or C₁ to C₃ alkoxy; R⁴ is H, halogen, NO₂, CN, or C₁ to C₃ alkyl;R⁵ is the five membered ring (v) or (vi) having the structure:

 wherein: U is O, S, or NH; X′ is halogen, CN, or NO₂, provided thatwhen U is NH, X is not CN; Y′ is H or C₁ to C₃ alkyl.
 7. The methodaccording to claim 1, wherein the antiprogestin compound is selectedfrom the group consisting of: a)6-(3-Chlorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one; b)6-(3-Methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;c)6-(2-Chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;d)6-(4-Chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;e) 6-(3-Chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;f) 6-(3-Chloro-phenyl)-4-ethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;and g)6-(3-Chloro-phenyl)-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; or apharmaceutically acceptable salt thereof.
 8. The method according toclaim 1, wherein the antiprogestin compound is selected from the groupconsisting of: a)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile;b) 4,4-Dimethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one;c)6-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;d)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile;e)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-nicotinonitrile;f)4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile;g)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile;h)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-methyl-thiophene-2-carbonitrile;i)4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile;and j)4,4-Diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one; or apharmaceutically acceptable salt thereof.
 9. The method according toclaim 1, wherein the antiprogestin compound is selected from the groupconsisting of: a)6-(3-Chlorophenyl)-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one; b)6-(3-Chlorophenyl)-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2-(1H)-one;c)6-(3-Chlorophenyl)-spiro-[4H-3,1-benzoxazine-4,1′-cyclopentane]-2(1H)-one;d)6-(3-Nitrophenyl)-spiro[4H-3,1-benzoxazine-4,1′-cyclohexan]-2(1H)-one;e)4-Allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;f)6-(3-Chlorophenyl)-4-methyl-4propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;and g)6-(3-Chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;or a pharmaceutically acceptable salt thereof.
 10. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a)6-(3-Chlorophenyl)-4-methyl-4-phenyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;b)4-Benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;c)6-(3-Chloro-phenyl)-4-cyclopropyl-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;d)6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;e)6-(3-Chloro-phenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;f)6-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;g)6-(3-Bromo-5-fluorophenyl)-1,4,4-trimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;h)6-Chloro-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;and i)6-(3-Methoxyphenyl)-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;or a pharmaceutically acceptable salt thereof.
 11. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a)6-(3-Acetyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;b)6-(3-Acetyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;c)6-(3-Benzoyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;d)4,4-Dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydrobenzo[d][1,3]oxazin-2-one;e)4-(4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile;f)6-(3-Bromo-5-fluoro-phenyl)-4,4-dicyclopropyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one;g)3-(4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile;h)6-(3-Bromo-5-methyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one;i)6-(3-Bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-one;and j)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methyl-benzonitrile;or a pharmaceutically acceptable salt thereof.
 12. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-trifluoromethoxy-benzonitrile;b)6-(3,5-difluoro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one;c)6-(3,5-dichloro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one;d)6-(3,5-Bis-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one;e)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methoxy-benzonitrile;f)6-(3-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;g)6-(3-Chloro-4-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;h)3-(1-Diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile;and i)3-Fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile;or a pharmaceutically acceptable salt thereof.
 13. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a) Phosphoric acid6-(3-cyano-5-fluoro-phenyl)-4,4-dimethyl-4H-benzo[d][1,3]oxazin-2-ylester diethyl ether; b)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-fluoro-benzonitrile;c)6-(3-Chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-one;d)6-(3-Bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;e)4,4-Dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one;f)6-(3-Ethynyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;g)3-[3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-phenyl]-propynenitrile;h)6-(3-Fluoro-5-nitro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;and i)6-(3-Chloro-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;or a pharmaceutically acceptable salt thereof.
 14. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a)3-Chloro-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile;b)6-(3,5-Dinitro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;c)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-isophthalonitrile;d)4,4-Dimethyl-6-(3-thiazol-2-yl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one;e)6-(3-Fluoro-5-methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;f)6-(3-Fluoro-5-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;g)6-(5-Bromo-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;h)6-(5-Bromo-1-oxy-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;and i)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile;or a pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a)4-(8-Fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile;b)3-Fluoro-5-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile;c)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-3-carbonitrile;d)2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-3-carbonitrile;e)6-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;f)6-(3-Fluoro-5-thiophen-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;g)4,4-Dimethyl-6-(5-nitro-1H-pyrrol-2-yl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one;and h)4,4-Dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;or a pharmaceutically acceptable salt thereof.
 16. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a)4,4-Dimethyl-6-(1-methyl-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one;b)4,4-Dimethyl-6-(1-methyl-5-nitro-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one;c)3-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-benzonitrile;d)3-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-5-fluorobenzonitrile;e)4-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-2-thiophenecarbonitrile;f)5-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-2-thiophenecarbonitrile;g)5-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexan]-6-yl)-4-methyl-2-thiophenecarbonitrile;h)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-ethyl-thiophene-2-carbonitrile;and i)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-n-propyl-thiophene-2-carbonitrile;or a pharmaceutically acceptable salt thereof.
 17. The method accordingto claim 1, wherein the antiprogestin compound is selected from thegroup consisting of: a)6-(4-Cyano-3-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-one;b)6-(4-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;c)6-(3,4-Difluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;d)6-(2-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one;e)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)phenylacetonitrile;f)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile;g)5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile;and h)3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile;or a pharmaceutically acceptable salt thereof.
 18. The method accordingto claim 1, wherein the progestational agent is selected from the groupconsisting of levonorgestrel, norgestrel, desogestrel,3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate,norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest,drospirenone, nomegestrol, and (17-deacetyl)norgestimate.
 19. The methodof contraception according to claim 1, which comprises: a) a first phaseof 21 daily dosage units, each daily dosage unit containing saidprogestational agent and ethinyl estradiol; b) a second phase of 3 dailydosage units, each daily dosage unit containing said antiprogestin andethinyl estradiol; and c) optionally, a third phase of 4 daily dosageunits of an orally and pharmaceutically acceptable placebo.
 20. Apharmaceutically useful kit adapted for daily oral administration whichcomprises: a) a first phase of from 18 to 21 daily dosage units of aprogestational agent equal in progestational activity to about 35 toabout 150 μg levonorgestrel and ethinyl estradiol at a daily dose rangeof from about 10 to about 35 μg; b) a second phase of from 1 to 7 dailydosage units of an antiprogestin of the structure:

 wherein: R¹ and R² are independent substituents selected from the groupconsisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^(A),and NR^(B)COR^(A); or R¹ and R² are fused to form: (i) a carbon-based 3to 8 membered saturated spirocyclic ring; (ii) a carbon-based 3 to 8membered spirocyclic ring having in its backbone one or morecarbon-carbon double bonds; or (iii) a 3 to 8 membered heterocyclic ringhaving in its backbone one to three heteroatoms selected from the groupconsisting of O, S and N; the spirocyclic rings of (i), (ii) and (iii)being optionally substituted by from 1 to 4 groups selected from thegroup consisting of fluorine, C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆thioalkyl, CF₃, OH, CN, NH₂, NH(C₁ to C₆ alkyl), and N(C₁ to C₆ alkyl)₂;R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(B) is H, C₁ to C₃alkyl, or substituted C₁ to C₃ alkyl; R³ is H, OH, NH₂, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, substituted C₃ to C₆alkenyl, alkynyl, substituted alkynyl, or COR^(C); R^(C) is H, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substitutedC₁ to C₃ aminoalkyl; R⁴ is H, halogen, CN, NO₂, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, alkynyl, substituted alkynyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ aminoalkyl, orsubstituted C₁ to C₆ aminoalkyl; R⁵ is (iv), (v), (vi), or (vii) (iv) asubstituted benzene ring having the substituents X, Y and Z:

 wherein: X is selected from the group consisting of halogen, CN, C₁ toC₃ alkyl, substituted C₁ to C₃ alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkoxy, substituted C₁ to C₃ thioalkoxy, amino, C₁to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone1 to 3 heteroatoms, COR^(D), OCOR^(D), and NR^(E)COR^(D); R^(D) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl; Y and Z are independent substituentsselected from the group consisting of H, halogen, CN, NO₂, amino,aminoalkyl, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkoxy;(v) a five membered ring having in its backbone 1, 2, or 3 heteroatomsselected from the group consisting of O, S, SO, and SO₂ and having oneor two independent substituents selected from the group consisting of H,halogen, CN, NO₂, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(F), and NR^(G)COR^(F); (vi) a five membered ring havingin its backbone 1, 2, or 3 NR⁶ heteroatoms and having one or twoindependent substituents selected from the group consisting of H,halogen, NO₂, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(F), and NR^(G)COR^(F); or (vii) a six membered ringhaving in its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂, and NR⁶ and having one or two independentsubstituents selected from the group consisting of H, halogen, CN, NO₂,amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(F),and NR^(G)COR^(F); R^(F) is H, C₁ to C₃ alkyl, substituted C₁ to C₃alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(G)is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R⁶ is H or C₁ to C₃alkyl; or pharmaceutically acceptable salt thereof; at a daily dose offrom about 2 to 50 mg; and c) a third phase of from 0 to 9 daily dosageunits of an orally and pharmaceutically acceptable placebo; wherein thetotal number of the daily dosage units in the first phase, second phaseand third phase equals
 28. 21. The pharmaceutically useful kit adaptedfor daily oral administration according to claim 22 which comprises: a)a first phase of 21 daily dosage units of said progestational agent andethinyl estradiol; b) a second phase of 3 daily dosage units of saidantiprogestin of formula I; and c) a third phase of 4 daily dosage unitsof an orally and pharmaceutically acceptable placebo.
 22. Apharmaceutically useful kit adapted for daily oral administration whichcomprises: a) a first phase of from 18 to 21 daily dosage units, eachdaily dosage unit comprising a progestational agent at a daily doseequal in progestational activity to from about 35 to about 150 μglevonorgestrel and ethinyl estradiol at a daily dose range of from about10 to about 35 μg; b) a second phase of from 1 to 7 daily dosage units,each daily dosage unit containing an antiprogestin of the structure:

 wherein: R¹ and R² are independent substituents selected from the groupconsisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^(A),and NR^(B)COR^(A); or R¹ and R² are fused to form: (i) a carbon-based 3to 8 membered saturated spirocyclic ring; (ii) a carbon-based 3 to 8membered spirocyclic ring having in its backbone one or morecarbon-carbon double bonds; or (iii) a 3 to 8 membered heterocyclic ringhaving in its backbone one to three heteroatoms selected from the groupconsisting of O, S and N; the spirocyclic rings of (i), (ii) and (iii)being optionally substituted by from 1 to 4 groups selected from thegroup consisting of fluorine, C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆thioalkyl, CF₃, OH, CN, NH₂, NH(C₁ to C₆ alkyl), and N(C₁ to C₆ alkyl)₂;R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(B) is H, C₁ to C₃alkyl, or substituted C₁ to C₃ alkyl; R³ is H, OH, NH₂, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, substituted C₃ to C₆alkenyl, alkynyl, substituted alkynyl, or COR^(C); R^(C) is H, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substitutedC₁ to C₃ aminoalkyl; R⁴ is H, halogen, CN, NO₂, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, alkynyl, substituted alkynyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ aminoalkyl, orsubstituted C₁ to C₆ aminoalkyl; R⁵ is (iv), (v), (vi), or (vii) (iv) asubstituted benzene ring having the substituents X, Y and Z:

 wherein: X is selected from the group consisting of halogen, CN, C₁ toC₃ alkyl, substituted C₁ to C₃ alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkoxy, substituted C₁ to C₃ thioalkoxy, amino, C₁to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone1 to 3 heteroatoms, COR^(D), OCOR^(D), and NR^(E)COR^(D); R^(D) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl; Y and Z are independent substituentsselected from the group consisting of H, halogen, CN, NO₂, amino,aminoalkyl, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkoxy;(v) a five membered ring having in its backbone 1, 2, or 3 heteroatomsselected from the group consisting of O, S, SO, and SO₂ and having oneor two independent substituents selected from the group consisting of H,halogen, CN, NO₂, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(F), and NR^(G)COR^(F); (vi) a five membered ring havingin its backbone 1, 2, or 3 NR⁶ heteroatoms and having one or twoindependent substituents selected from the group consisting of H,halogen, NO₂, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(F), and NR^(G)COR^(F); or (vii) a six membered ringhaving in its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂, and NR⁶ and having one or two independentsubstituents selected from the group consisting of H, halogen, CN, NO₂,amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(F),and NR^(G)COR^(F); R^(F) is H, C₁ to C₃ alkyl, substituted C₁ to C₃alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(G)is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R⁶ is H or C₁ to C₃alkyl; or pharmaceutically acceptable salt thereof; at a concentrationof from 2 to 50 mg and ethinyl estradiol at a concentration of fromabout 10 to about 35 μg; and c) a third phase of from 0 to 9 dailydosage units of an orally and pharmaceutically acceptable placebo;wherein the total number of the daily dosage units in the first phase,second phase and third phase equals
 28. 23. The pharmaceutically usefulkit adapted for daily oral administration according to claim 22, whichcomprises: a) a first phase of 21 daily dosage units, each daily dosageunit containing said progestational agent and ethinyl estradiol; b) asecond phase of 3 daily dosage units, each daily dosage unit containingsaid antiprogestin of formula I and ethinyl estradiol; and c) a thirdphase of 4 daily dosage units of an orally and pharmaceuticallyacceptable placebo.
 24. A method of contraception which comprisesadministering to a female of child bearing age over a period of 28consecutive days: a) a first phase of from 18 to 21 daily dosage unitscontaining a progestational agent at a daily dose equal inprogestational activity to from about 35 to about 150 μg levonorgestreland ethinyl estradiol at a daily dose range of from about 10 to about 35μg; b) a second phase of from 1 to 7 daily dosage units, each dailydosage unit containing an antiprogestin of the formula:

 wherein: R¹ is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heterocyclic, substituted heterocyclic, COR^(A), or NR^(B)COR^(A); R² isH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, COR^(A), or NR^(B)COR^(A); or R¹ and R² are fused to form:(i) a carbon-based 3 to 8 membered saturated spirocyclic ring; (ii) acarbon based 3 to 8 membered spirocyclic ring having in its backbone ormore carbon-carbon double bonds; or (iii) a carbon-based 3 to 8 memberedheterocyclic ring having in its backbone one to three heteroatomsselected from the group consisting of O, S and N; the spirocyclic ringsof (i), (ii) and (iii) being optionally substituted by from 1 to 4groups selected from the group consisting of fluorine, C₁ to C₆ alkyl,C₁ to C₆ alkoxy, C₁ to C₆ thioalkyl, CF₃, OH, CN, NH₂, NH(C₁ to C₆alkyl), and N(C₁ to C₆ alkyl)₂; R^(A) is H, C₁ to C₃ alkyl, substitutedC₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;R^(B) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R³ is H, OH,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl,substituted C₃ to C₆ alkenyl, alkynyl, substituted alkynyl, or COR^(C);R^(C) is H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, aryl,substituted aryl, C₁ to C₄ alkoxy, substituted C₁ to C₄ alkoxy, C₁ to C₄aminoalkyl, or substituted C₁ to C₄ aminoalkyl; R⁴ is H, halogen, CN,NO₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ aminoalkyl, or substitutedC₁ to C₆ aminoalkyl; R⁵ is (iv), (v), (vi), or (vii): (iv) a substitutedbenzene ring of the structure:

X is selected from the group consisting of halogen, CN, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkoxy, substituted C₁ to C₃ thioalkoxy, amino, C₁to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone1 to 3 heteroatoms, COR^(D), OCOR^(D) and NR^(E)COR^(D); R^(D) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl; Y and Z are independent substituentsselected from the group consisting of H, halogen, CN, NO₂, C₁ to C₃alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkoxy; (v) a five memberedring having in its backbone 1, 2, or 3 heteroatoms selected from thegroup consisting of O, S, SO, and SO₂ and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂, amino, C₁ to C₃ alkyl, and C₁ to C₃ alkoxy; (vi) afive membered ring having in its backbone 1, 2, or 3 NR⁶ heteroatoms andcontaining one or two independent substituents selected from the groupconsisting of H, halogen, NO₂, amino, C₁ to C₃ alkyl, and C₁ to C₃alkoxy; or (vii) a six membered ring having in its backbone 1, 2, or 3heteroatoms selected from the group consisting of O, S, SO, SO₂ and NR⁶and containing one or two independent substituents selected from thegroup consisting of H, halogen, CN, NO₂, amino, C₁ to C₃ alkyl, and C₁to C₃ alkoxy; R⁶ is H, or C₁ to C₃ alkyl; or pharmaceutically acceptablesalt thereof; at a concentration of from 2 to 50 mg and ethinylestradiol at a concentration of from about 10 to about 35 μg; and c)optionally, a third phase of daily dosage units of an orally andpharmaceutically acceptable placebo, the total of the daily dosage unitsbeing
 28. 25. A method of contraception which comprises administering toa female of child bearing age over a period of 28 consecutive days: a) afirst phase of from 18 to 21 daily dosage units containing aprogestational agent at a daily dose equal in progestational activity tofrom about 35 to about 150 μg levonorgestrel and ethinyl estradiol at adaily dose range of from about 10 to about 35 μg; b) a second phase offrom 1 to 7 daily dosage units, each daily dosage unit containing anantiprogestin of the formula:

 wherein: R¹═R² and are selected from the group consisting of C₁ to C₃alkyl and substituted C₁ to C₃ alkyl; or R¹ and R² are fused to form acarbon-based 3 to 6 membered saturated spirocyclic ring; R³ is H, OH,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, or COR^(C); R^(C) is H,C₁ to C₄ alkyl, or C₁ to C₄ alkoxy; R⁴ is H, halogen, CN, NO₂, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, or substituted C₁ toC₃ alkoxy; R⁵ is (i), (ii), (iii), or iv): (i) a substituted benzenering of the structure:

 wherein: X is halogen, CN, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁ toC₃ perfluoroalkyl, 5 membered heterocyclic ring containing in itsbackbone 1 to 3 heteroatoms, or C₁ to C₃ thioalkoxy; Y is H, halogen,CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃ thioalkoxy; (ii) afive membered ring of the structure:

 wherein: U is O or S; X′ is selected from the group consisting ofhalogen, CN, NO₂, C₁ to C₃ alkyl and C₁ to C₃ alkoxy; Y′ is selectedfrom the group consisting of H and C₁ to C₄ alkyl; (iii) the fivemembered ring of the structure:

 wherein: U is NR⁶; X′ is selected from the group consisting of halogen,NO₂, C₁ to C₃ alkyl and C₁ to C₃ alkoxy; Y′ is selected from the groupconsisting of H and C₁ to C₃ alkyl; or (iv) a six membered ring of thestructure:

 wherein: X¹ is N or CX²; X² is halogen, CN, alkoxy, or NO₂; R⁶ is H, C₁to C₃ alkyl, or C₁ to C₄ CO₂alkyl; or pharmaceutically acceptable saltthereof; at a concentration of from 2 to 50 mg and ethinyl estradiol ata concentration of from about 10 to about 35 μg; and c) optionally, athird phase of daily dosage units of an orally and pharmaceuticallyacceptable placebo, the total of the daily dosage units being
 28. 26.The method according to claim 25, wherein the antiprogestin is6-(3-Cyano-5-fluoro-phenyl)-4,4-dimethyl-2-oxo-4H-benzo[d][1,3]oxazine-1-carboxylicacid tert-butyl ester;2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1-carboxylicacid tert-butyl ester;2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-nitro-pyrrole-1-carboxylicacid tert-butyl ester; and5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-n-butyl-thiophene-2-carbonitrile;5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-n-butyl-thiophene-2-carbonitrile;or a pharmaceutically acceptable salt thereof.
 27. A method ofcontraception which comprises administering to a female of child bearingage over a period of 28 consecutive days: a) a first phase of from 18 to21 daily dosage units containing a progestational agent at a daily doseequal in progestational activity to from about 35 to about 150 μglevonorgestrel and ethinyl estradiol at a daily dose range of from about10 to about 35 μg; b) a second phase of from 1 to 7 daily dosage units,each daily dosage unit containing an antiprogestin of the formula:

 wherein: R¹ and R² are CH₃ or R¹ and R² are fused to form acarbon-based 6 membered spirocyclic saturated ring R³ is H, OH, NH₂,CH₃, substituted CH₃, or COR^(A); R^(A) is H, C₁ to C₃ alkyl, or C₁ toC₄ alkoxy; R⁴ is H, halogen, NO₂, CN, or C₁ to C₃ alkyl; R⁵ is (i) or(ii): (i) a substituted benzene ring of the formula:

 wherein: X is selected from the group consisting of halogen, CN,methoxy, NO₂, 5-membered heterocyclic ring; wherein said 5-memberedheterocyclic ring is 2-thiazole; Y is H or halogen; wherein said halogenis F; or (ii) a five membered ring of the structure:

 wherein: U is O, S, or NH; X′ is halogen, CN, or NO₂, provided thatwhen U is NH, X is not CN; Y′ is H or C₁ to C₄ alkyl or pharmaceuticallyacceptable salt thereof; at a concentration of from 2 to 50 mg andethinyl estradiol at a concentration of from about 10 to about 35 μg;and c) optionally, a third phase of daily dosage units of an orally andpharmaceutically acceptable placebo, the total of the daily dosage unitsbeing 28.